Dual nk1/nk3 receptor antagonists

ABSTRACT

The present invention provides a method for the treatment of schizophrenia which comprises administering a compound of formula 
     
       
         
         
             
             
         
       
         
         
           
             wherein the substituents are as described herein or a pharmaceutically active acid-addition salt thereof. In particular, the invention provides methods for treating both positive and negative symptoms of schizophrenia through dual inhibition of NK1 and NK3 receptors. The invention also provides novel compounds with formula I and methods for preparing compounds of the invention.

PRIORITY TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/361,569, filed Jan. 29, 2009, now pending; which is a continuation ofU.S. application Ser. No. 10/884,707, filed Jul. 2, 2004, now pending;which claims the benefit of European Application No. 03014513.0, filedJul. 3, 2003. The entire contents of the above-identified applicationsare hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Schizophrenia is one of the major neuropsychiatric disorders,characterized by severe and chronic mental impairment. This devastatingdisease affects about 1% of the world's population. Symptoms begin inearly adulthood and are followed by a period of interpersonal and socialdysfunction. Schizophrenia manifests as auditory and visualhallucinations, paranoia, delusions (positive symptoms), blunted affect,depression, anhedonia, poverty of speech, memory and attention deficitsas well as social withdrawal (negative symptoms).

For decades scientists and clinicians have made efforts with the aim ofdiscovering an ideal agent for the pharmacological treatment ofschizophrenia. However, the complexity of the disorders, due to a widearray of symptoms, has hampered those efforts. There are no specificfocal characteristics for the diagnosis of schizophrenia and no singlesymptom is consistently present in all patients. Consequently, thediagnosis of schizophrenia as a single disorder or as a variety ofdifferent disorders has been discussed but not yet resolved. The majordifficulty in the development of a new drug for schizophrenia is thelack of knowledge about the cause and nature of this disease. Someneurochemical hypotheses have been proposed on the basis ofpharmacological studies to rationalize the development of acorresponding therapy: the dopamine, the serotonin and the glutamatehypotheses. But taking into account the complexity of schizophrenia, anappropriate multireceptor affinity profile might be required forefficacy against positive and negative signs and symptoms. Furthermore,an ideal drug against schizophrenia would preferably have a low dosageallowing once-per-day dosage, due to the low adherence of schizophrenicpatients.

In recent years clinical studies with selective NK1 and NK2 receptorantagonists appeared in the literature showing results for the treatmentof emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2and NK1). The most exciting data were produced in the treatment ofchemotherapy-induced emesis, nausea and depression with NK1 and inasthma with NK2-receptor antagonists. In contrast, no clinical data onNK3 receptor antagonists have appeared in the literature until 2000.Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identifiedpotent and selective non-peptide antagonist described for the NK3tachykinin receptor for the potential treatment of schizophrenia, whichwas reported in the literature (Current Opinion in InvestigationalDrugs, 2001, 2(7), 950-956 and Psychiatric Disorders Study 4,Schizophrenia, June 2003, Decision Resources, Inc., Waltham, Mass.). Theproposed drug SR 142,801 has been shown in a phase II trial as active onpositive symptoms of schizophrenia, such as altered behavior, delusion,hallucinations, extreme emotions, excited motor activity and incoherentspeech, but inactive in the treatment of negative symptoms, which aredepression, anhedonia, social isolation or memory and attentiondeficits.

The neurokinin-3 receptor antagonists have been described as useful inpain or inflammation, as well as in schizophrenia, Exp. Opinion. Ther.Patents (2000), 10(6), 939-960 and Current Opinion in InvestigationalDrugs, 2001, 2(7), 950-956956 and Psychiatric Disorders Study 4,Schizophrenia, June 2003, Decision Resources, Inc., Waltham, Mass.).

In addition, EP 1 192 952 describes a pharmaceutical compositioncontaining a combination of a NK3 receptor antagonist and a CNSpenetrant NK1 receptor antagonist for the treatment of depression andanxiety.

Now it has been found that the combination of the antidepressant, moodenhancing properties of NK1 receptor antagonism and the antipsychoticsymptoms of NK3 receptor antagonism are suitable to treat both positiveand negative symptoms in schizophrenia.

This advantage may be realized in the administration of an ideal drugagainst schizophrenia.

Some of the compounds of formula I are described in EP 1035115, WO02/08232 or WO 02/16324.

They have been described as active at the NK1 receptor for the treatmentof diseases related to this receptor, such as inflammatory conditionsincluding migraine, rheumatoid arthritis, asthma, and inflammatory boweldisease as well as mediation of the emetic reflex and the modulation ofcentral nervous system (CNS) disorders such as Parkinson's disease,anxiety, pain, headache, especially migraine, Alzheimer's disease,multiple sclerosis, attenuation of morphine withdrawal, cardiovascularchanges, oedema, such as oedema caused by thermal injury, chronicinflammatory diseases such as rheumatoid arthritis, asthma/bronchialhyperreactivity and other respiratory diseases including allergicrhinitis, inflammatory diseases of the gut including ulcerative colitisand Crohn's disease, ocular injury and ocular inflammatory diseases.

The neurokinin-1 receptor antagonists are further useful for thetreatment of motion sickness, for treatment induced vomiting or for thetreatment of psychoimmunologic or psychosomatic disorders, see Neurosci.Res., 1996, 7, 187-214, Can. J. Phys., 1997, 75, 612-621, Science, 1998,281, 1640-1645, Anton. Pharmacol., 13, 23-93, 1993, WO 95/16679, WO95/18124 and WO 95/23798, The New England Journal of Medicine, Vol. 340,No. 3 190-195, 1999, U.S. Pat. No. 5,972,938.

SUMMARY OF THE INVENTION

The present invention relates to the use of compounds of formula I andpharmaceutically acceptable salts thereof for the treatment of positiveand negative symptoms in schizophrenia, novel compounds of formulas I,pharmaceutically active acid-addition salts thereof, all stereoisomericforms of the compounds of formula I, including each of the individualenantiomers and mixtures thereof, the preparation of the above-mentionednovel compounds, medicaments containing them and their manufacture aswell as the use of the above-mentioned compounds in the control orprevention of illnesses, especially of illnesses and disorders of thekind referred to earlier or in the manufacture of correspondingmedicaments.

Thus, in one embodiment the invention provides a method of treatingschizophrenia which comprises administering a compound of formula

wherein

-   R¹ is aryl, unsubstituted or substituted by one or more substituents    selected from the group consisting of alkyl, alkoxy, halogen,    —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl, —C(O)NR′R″,    —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl,    -   or    -   is heteroaryl, selected from the group consisting of pyridin-2-        or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted        or substituted by alkyl, halogen or alkoxy;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently    -   hydrogen,    -   —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or        —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each        carbon atom may be the same or different from each other,    -   —C_(b)-alkyl,    -   —C(O)H,    -   —(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy,    -   —(CH₂)_(c)NR′R″,    -   —(CH₂)_(c)NR′C(O)-alkyl,    -   —(CH₂)_(d)NR′S(O)₂-alkyl,    -   —(CH₂)_(d)S(O)-alkyl,    -   —(CH₂)_(d)S-alkyl,    -   —(CH₂)_(d)S(O)₂-alkyl;    -   —(CH₂)_(d)S(O)₂—NR′R″-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl; or-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring    -   with —(CH₂)_(e)—, which is unsubstituted or substituted        -   by one or more substituents selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl, or —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with    -   —(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            —NR′R″, wherein R′ and R″ are as described above or may form            together with the N-atom to which they are attached a ring            with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—S(O)_(f)—(CH₂)_(c)—, which is unsubstituted or        substituted        -   by one or more substituents selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″,    -   or with    -   —CH₂CH═CH—CH₂—, which is unsubstituted or substituted        -   by one or more substituents selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″;    -   or with    -   —(CH₂)₂—S(O)₂N(CH₃)—CH₂,    -   or with    -   —S(O)—O—(CH₂)_(g)—-   or —NR⁴R⁵ is

-   a is 0 or 1;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3;-   e is 3, 4, or 5;-   f is 0, 1, or 2; and-   g is 2 or 3;    or a pharmaceutically active acid-addition salt thereof.

The compounds of formula I may contain some asymmetric carbon atoms.Accordingly, the present invention includes all stereoisomeric forms ofthe compounds of formula I, including each of the individual enantiomersand mixtures thereof.

The compounds of formula I and their salts are characterized by valuabletherapeutic properties. It has surprisingly been found that thecompounds of formula I show a high affinity simultaneously to both theNK1 and the NK3 receptors (dual NK1/NK3 receptor antagonists), useful inthe treatment of schizophrenia.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “lower alkyl” denotes a straight- orbranched-chain alkyl group containing from 1-4 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl andthe like. The term “alkyl” denotes a straight- or branched-chain alkylgroup containing from 1-7 carbon atoms.

The terms “lower alkoxy” and “alkoxy” denote a group wherein the alkylresidues are as defined above, and which is attached via an oxygen atom.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “cycloalkyl” denotes a saturated carbocyclic group containing3-6 carbon atoms.

The term “aryl” means a monovalent cyclic aromatic hydrocarbon groupconsisting of one or more fused rings in which at least one ring isaromatic in nature. Examples of aryl radicals include, but are notlimited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, and thelike. The preferred aryl group is phenyl.

“Heteroaryl” means a monovalent aromatic carbocyclic group having one ormore rings incorporating one, two, or three heteroatoms within the ringwherein the heteroatoms are chosen from nitrogen, oxygen, or sulfur.Examples of heteroaryl radicals include, but are not limited to,imidazolyl, isoxazolyl, thiazolyl, pyrazinyl, thiophenyl, furanyl,pyranyl, pyridinyl, quinolinyl, isoquinolinyl, benzofuryl,benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl,benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl,naphtyridinyl, and the like. Preferred heteroaryl groups are isoxazolyland pyridinyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salt” embraces saltswith inorganic and organic acids, such as hydrochloric acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaricacid, maleic acid, acetic acid, succinic acid, tartaric acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

In one embodiment the invention provides a method of treatingschizophrenia which comprises administering a compound of formula

wherein

-   R¹ is aryl, unsubstituted or substituted by one or more substituents    selected from the group consisting of alkyl, alkoxy, halogen,    —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl, —C(O)NR′R″,    —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl,    -   or    -   is heteroaryl, selected from the group consisting of pyridin-2-        or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted        or substituted by alkyl, halogen or alkoxy;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently    -   hydrogen,    -   —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or        —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each        carbon atom may be the same or different from each other,    -   —C_(b)-alkyl,    -   —C(O)H,    -   —(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy,    -   —(CH₂)_(c)NR′R″,    -   —(CH₂)_(c)NR′C(O)-alkyl,    -   —(CH₂)_(c)NR′S(O)₂-alkyl,    -   —(CH₂)_(d)S(O)-alkyl,    -   —(CH₂)_(d)S-alkyl,    -   —(CH₂)_(d)S(O)₂-alkyl, or    -   —(CH₂)_(d)S(O)₂—NR′R″;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl; or-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring    -   with —(CH₂)_(e)—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl, or —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—S(O)_(f)—(CH₂)_(c)—, which is unsubstituted or        substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(o)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″,    -   or with    -   —CH₂CH═CH—CH₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO,            and —NR′R″, wherein R′ and R″ are as described above or may            form together with the N-atom to which they are attached a            ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl,            —(CH₂)_(d)—S-alkyl, —(CH₂)_(d)—S(O)₂—NR′R″,            —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; or with            —(CH₂)₂—S(O)₂N(CH₃)—CH₂, or with —S(O)—O—(CH₂)_(g)—;-   or —NR⁴R⁵ is

-   a is 0 or 1;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3;-   e is 3, 4, or 5;-   f is 0, 1, or 2; and-   g is 2 or 3;    or a pharmaceutically active acid-addition salt thereof.

In another embodiment, the invention provides a method of treatingschizophrenia which comprises administering a compound of 1 formula

wherein

-   R¹ is aryl, unsubstituted or substituted by one or more substituents    selected from the group consisting of lower alkyl, lower alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-lower alkyl, —S(O)₂-lower    alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-lower alkyl, and —NR′S(O)₂-lower    alkyl,    -   or    -   is heteroaryl, selected from the group consisting of pyridin-2-        or 3-yl, imidazolyl, and oxazolyl, each of which is        unsubstituted or substituted by lower alkyl, halogen or lower        alkoxy;-   R² and R³ are each independently hydrogen, halogen, lower alkyl,    lower alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently    -   hydrogen,    -   —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or        —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-lower alkyl, wherein R′ and R″ on        each carbon atom may be the same or different from each other,    -   —C_(b)-alkyl,    -   —C(O)H, —(CH₂)_(d)cycloalkyl, unsubstituted or substituted by        hydroxy,    -   —(CH₂)_(c)NR′C(O)-lower alkyl, —(CH₂)_(c)NR′S(O)₂-lower alkyl,        or    -   —(CH₂)_(d)S(O)₂-lower alkyl;-   R′ is hydrogen, lower alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-lower    alkyl, —C(O)-cycloalkyl or S(O)₂-lower alkyl;-   R″ is hydrogen or lower alkyl;-   or-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with    -   —(CH₂)_(e)—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O,            and —NR′R″, wherein R′ and R″ may form together with the            N-atom to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl, or            —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″, or with    -   —(CH₂)_(c)—S(O)_(f)—(CH₂)₂—, which is unsubstituted or        substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″,    -   or with    -   —CH₂CH═CH—CH₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂) d-pyrrolidinyl or            —C(O)NR′R″;-   a is 0 or 1;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3;-   e is 3, 4 or 5;-   f is 0, 1, or 2; and-   g is 2 or 3;    or a pharmaceutically active acid-addition salts thereof as    described above.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R¹, R⁴ and R⁵ have the definitions as described informula I-1 and R² and R³ are both CF₃.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)_(e)—, which is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, —NR′R″,—(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-loweralkyl, —(CH₂)_(d)— pyrrolidinyl, and —C(O)NR′R″.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₄—, wherein the ring is monosubstituted by —CH₂OH or disubstituted by hydroxy and —CH₂OH. Examplesof such compounds include

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₄—, wherein the ring isdisubstituted by NHC(O)CH₃ and —CH₂OH. An example of such compounds is(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₄—, wherein the ring isdisubstituted by ═O and —CH₂OH. Examples of such compounds are

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1 wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₄—, wherein the ring is di- ortri-substituted by halogen and —CH₂OH. Examples of such compounds are

-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ are each independently hydrogen,—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-lower alkyl, wherein R′ and R″ on eachcarbon atom may be the same or different from each other, or are—C_(b)-alkyl, —C(O)H, —(CH₂)_(d)cycloalkyl which is unsubstituted orsubstituted by hydroxy, —(CH₂)_(c)NR′C(O)-lower alkyl,—(CH₂)_(c)NR′S(O)₂-lower alkyl, —(CH₂)_(d)S(O)₂-lower alkyl,C(O)(CH₂)_(d)OH; R′ is hydrogen, lower alkyl, —(CH₂)_(d)OH, —C(O)-loweralkyl, —C(O)-cycloalkyl or S(O)₂-lower alkyl; and R″ is hydrogen orlower alkyl.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ are each independently hydrogen,—CH(CH₂OH)CH₂OH or —(CH₂)_(c)OH. Examples of such compounds are

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-{6-[bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)_(c)—O—(CH₂)₂—, which isunsubstituted or substituted by one or more substituents selected fromthe group consisting of lower alkyl, halogen, (CR′R″)_(d)OH, ═O, —NR′R″,—(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-loweralkyl, —(CH₂)_(d)— pyrrolidinyl and —C(O)NR′R″.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₂—O—(CH₂)₂—, wherein the ring issubstituted by —CH₂OH. Examples of such compounds are

-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (R)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)C—S(O)_(f)—(CH₂)₂—, which isunsubstituted or substituted by one or more substituents selected fromthe group consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O,—NR′R″, —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-loweralkyl, —(CH₂)_(d)— pyrrolidinyl and —C(O)NR′R″.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₂—S(O)₂—(CH₂)₂—, wherein the ring ismono-substituted by —CH₂OH. Examples of such compounds are

-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R¹, R⁴ and R⁵ have the definitions as describedabove and R² and R³ are other than di-CF₃.

In another embodiment of the invention, the method employs a compound offormula I-1, wherein R⁴ and R⁵ form together with the N-atom to whichthey are attached a ring with —(CH₂)₄— wherein the ring is monosubstituted by —CH₂OH or disubstituted by OH and —CH₂OH. Examples ofsuch compounds are

-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   (2S,4R)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention provides a compound of formula

wherein

-   R¹ is aryl, unsubstituted or substituted by one or more substituents    selected from the group consisting of lower alkyl, lower alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-lower alkyl, —S(O)₂-lower    alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-lower alkyl, and —NR′S(O)₂-lower    alkyl,    -   or    -   is heteroaryl, selected from the group consisting of pyridin-2-        or 3-yl, imidazolyl, and oxazolyl, each of which is        unsubstituted or substituted by lower alkyl, halogen or lower        alkoxy;-   R² and R³ are each independently hydrogen, halogen, lower alkyl,    lower alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently    -   hydrogen,    -   —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or        —(CR′R″)₁—(CR′R″)—(CR′R″)_(a)-lower alkyl, wherein R′ and R″ on        each carbon atom may be the same or different from each other,    -   —C_(b)-alkyl,    -   —C(O)H, —(CH₂)_(d)cycloalkyl, unsubstituted or substituted by        hydroxy,    -   —(CH₂)_(c)NR′C(O)-lower alkyl, —(CH₂)_(c)NR′S(O)₂-lower alkyl,        or    -   —(CH₂)_(d)S(O)₂-lower alkyl;-   R′ is hydrogen, lower alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-lower    alkyl, —C(O)-cycloalkyl or S(O)₂-lower alkyl;-   R″ is hydrogen or lower alkyl;    -   or-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with    -   —(CH₂)_(e)—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O,            and —NR′R″, wherein R′ and R″ may form together with the            N-atom to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl, or            —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″,    -   or with    -   —(CH₂)_(c)—S(O)_(f)—(CH₂)₂—, which is unsubstituted or        substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″,    -   or with    -   —CH₂CH═CH—CH₂—, which is unsubstituted or substituted        -   by one or more substituents, selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower            alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″;-   a is 0 or 1;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3;-   e is 3, 4 or 5;-   f is 0, 1, or 2; and-   g is 2 or 3;    or a pharmaceutically active acid-addition salts thereof as    described above.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ are eachindependently hydrogen, —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH, or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-lower alkyl, wherein R′ and R″ on eachcarbon atom may be the same or different from each other, or areC_(b)-alkyl. Examples of these compounds are

-   N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[ethyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-propyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[butyl-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2,3-dihydroxy-propyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(1-hydroxymethyl-3-methyl-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-2-methyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-{6-[bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[(2-hydroxy-ethyl)-propyl-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-propyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-propyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[hexyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-pentyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-1-hydroxymethyl-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl, R⁴ is hydrogen and R⁵is —(CH₂)_(d)-cycloalkyl, unsubstituted or substituted by hydroxy.Examples of these compounds are

-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1RS,2RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl, R⁴ is hydrogen and R⁵is —(CH₂)_(c)NR′C(O)-lower alkyl or —(CH₂)_(d)S(O)₂-lower alkyl.Examples of such compounds are

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   N-[6-(2-acetylamino-ethylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)₄—, which ring is substituted by one or two groups —(CR′R″)_(d)OH.Examples of such compounds are

-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-difluoro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-difluoro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide,-   (S)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2R,5R)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-dimethylamino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,5-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-4-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-amino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methylsulfanyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methanesulfonyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-2-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-4-yl]-benzamide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-cyano-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-difluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide.-   In another embodiment, the invention is a compound of formula I-1,    wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ form    together with the N-atom to which they are attached a ring with    —(CH₂)₄—, which ring is substituted by one to three substituents    selected from the group consisting of —NR′R″, —(CH₂)_(d)—C(O)-lower    alkyl, CH₂OH, —(CH₂)_(d)-pyrrolidinyl, —(CH₂)_(d)—S(O)₂-lower alkyl,    ═O, halogen and —(CH₂)_(d)OC(O)NR′R″. Examples of such compounds are-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (RS)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-methanesulfonyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide,-   (S)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-[2-(acetylamino-methyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide    or-   (S)-dimethyl-carbamic acid    1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-pyrrolidin-2-ylmethyl    ester.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(h)—, which ring is mono- or di-substituted by —(CH₂)_(d)OH or—NR′R″, wherein h is 3 or 5. Examples of such compounds are

-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[4-amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   N-[4-acetylamino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-azetidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,5-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3S,5R)-5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-2-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide    and-   (2RS,3RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(g)—NR′—(CH₂)₂—, which is unsubstituted or mono- ordi-substituted by —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —NR′R″ or ═O. Examples of such compounds are

-   N-[6-(4-acetyl-piperazin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(4-acetyl-[1,4]diazepan-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-oxo-[1,4]diazepan-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with —(CH₂)₂,—O—(CH₂)₂—, which is unsubstituted or mono- or -di-substituted by—(CR′R″)_(d)OH. Examples of such compounds are

-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(c)—S(O)_(f)—(CH₂)₂—, which is unsubstituted or mono- ordi-substituted by —(CR′R″)_(d)OH Examples of such compounds are

-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶_thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted phenyl as described above andR⁴ and R⁵ form together with the N-atom to which they are attached aring with —CH₂CH═CH—CH₂—, which is unsubstituted or mono-substituted by,—(CR′R″)_(d)OH. One such compound is

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

In another embodiment, the invention is a compound of formula I-1,wherein R¹ is unsubstituted or substituted heteroaryl as describedabove. Examples of such compounds are

-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,5-dimethyl-isoxazol-4-yl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2,6-dimethoxy-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   N-{6′-[bis-(2-hydroxy-ethyl)-amino]-2-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   N-{6′-[bis-(2-hydroxy-ethyl)-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-{6′-[(2-hydroxy-ethyl)-methyl-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-N-methyl-isobutyramide.

Preferred is the use of compounds of formula I, wherein R¹, R⁴ and R⁵have the definitions as described above and R² and R³ are both CF₃.

Further preferred is the use of compounds of formula I, wherein R⁴ andR⁵ form together with the N-atom to which they are attached a ring with—(CH₂)_(e)—, which ring is unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, halogen, CF₃,—(CR′R″)_(d)OH, ═O, and —NR′R″, wherein R′ and R″ may form together withthe N-atom to which they are attached a ring with —(CH₂)_(e), orsubstituted by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂—alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″.

Preferred is also the use of compounds of formula I, wherein R⁴ and R⁵form together with the N-atom to which they are attached a ring with—(CH₂)_(e)—, wherein the ring is mono or di-substituted by hydroxy,—CH₂OH or —C(O)H. Examples of such compounds are

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-formyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide    and    (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide.

Preferred are further compounds of formula I, wherein R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(e)—, wherein the ring is mono or di-substituted by NH₂,NHS(O)₂CH₃, NCH₃S(O)₂CH₃, N(CH₂CH₃)S(O)₂CH₃, NHC(O)CH₃ and —CH₂OH.Examples of such compounds are

-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-(methanesulfonyl-methyl-amino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(ethyl-methanesulfonyl-amino)-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

A further preferred group of compounds are further those, wherein R⁴ andR⁵ form together with the N-atom to which they are attached a ring with—(CH₂)₄— and wherein the ring is disubstituted by ═O and —CH₂OH, forexample the following compounds:

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

Compounds of formula I, wherein R⁴ and R⁵ form together with the N-atomto which they are attached a ring with —(CH₂)₄—, wherein the ring is di-or tri-substituted by halogen and —CH₂OH, are also preferred. Thefollowing compounds relate to this group:

-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

A further preferred group of compounds are those, wherein R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(e)—, wherein the ring is substituted by CH₂S(O)₂CH₃, CH₂SCH₃ orCH₂S(O)CH₃. Examples of such compounds are

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(RS)-3-((RS)-methanesulfinylmethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide    and-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

Other preferred compounds of formula I are those, wherein R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(e)—, wherein the ring is substituted by S(O)₂CH₃, SCH₃, S(O)CH₃or S(O)₂N(CH₃)₂, for example the following compounds:

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-dimethylsulfamoyl-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methylsulfanyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfinyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

Compounds, wherein —NR⁴R⁵ is

and R′ is as described in claim 1, are further preferred, whichcompounds are

-   (1S,3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (rac)-(1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfinyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-dioxo-1-oxa-4λ⁶-thia-8-aza-spiro[4.5]dec-8-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-5-thia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(5,5-dioxo-1-oxa-5λ⁶-thia-9-aza-spiro[5.5]undec-9-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,4,4-tetraoxo-1λ⁶,4λ⁶-dithia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,5,5-tetraoxo-1λ⁶,    5λ⁶-dithia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[(1S,5R)-4-(4-fluoro-2-methyl-phenyl)-6-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(8,8-dioxo-8λ⁶-thia-3-aza-bicyclo[3.2.1]oct-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-((1S,4S)-5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (1R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(8-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

Another group of preferred compounds of formula I are those wherein R⁴and R⁵ are each independently hydrogen;—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each carbonatom may be the same or different from each other; —C_(b)-alkyl; —C(O)H;—(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy; or is—(CH₂)_(c)NR′R″, —(CH₂)_(c)NR′C(O)-alkyl, —(CH₂)_(c)NR′S(O)₂-alkyl,—(CH₂)_(d)S(O)-alkyl, —(CH₂)_(d)S-alkyl, —(CH₂)_(f)S(O)₂-alkyl or—(CH₂)_(d)S(O)₂—NR′R″.

Especially preferred compounds from this group are those, wherein R⁴ andR⁵ are each independently hydrogen, —CH(CH₂OH)CH₂OH or —(CH₂)_(c)OH, forexample,

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-{6-[bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

Compounds of formula I, wherein R⁴ and R⁵ are each independentlyhydrogen, (CH₂)₂SCH₃, (CH₂)₂S(O)₂CH₃ or (CH₂)₂S(O)₂NHCH₃ are alsopreferred. Examples of such compounds are

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfamoyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

Other preferred compounds are those, wherein R⁴ and R⁵ are eachindependently hydrogen, (CH₂)₂NH₂, (CH₂)₂NHS(O)₂CH₃ or (CH₂)₂NHC(O)CH₃,for example,

-   N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylamino-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   N-[6-(2-acetylamino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

Preferred are further compounds of formula I, wherein R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituent selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or may form together with the N-atom to which they areattached a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″.

To this group relate compounds, wherein R⁴ and R⁵ form together with theN-atom to which they are attached a ring with —(CH₂)₂—O—(CH₂)₂—, whereinthe ring is unsubstituted or substituted by —CH₂OH, for example,

-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide.

Another preferred group are compounds of formula I, wherein R⁴ and R⁵form together with the N-atom to which they are attached a ring with—(CH₂)_(c)—S(O)_(f)—(CH₂)_(v)—, which is unsubstituted or substituted byone or more substituents selected from the group consisting of alkyl,halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″are as described above or may form together with the N-atom to whichthey are attached a ring with —(CH₂)_(e), or by—(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″.

Especially preferred compounds from this group are those wherein R⁴ andR⁵ form together with the N-atom to which they are attached a ring with—(CH₂)₂—S(O)₂—(CH₂)₂—, wherein the ring is unsubstituted or substitutedby —CH₂OH or methyl. Examples of such compounds are

-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiazolidin-3-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1RS,4RS)- or    (1RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    (Diastereomeric racemate of Example 349),-   (1RS,4SR)- or    (1RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    (Diastereomeric racemate of Example 348),-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1,1-dioxo-1λ⁶-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (+)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (−)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,3]thiazinan-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methyl-1,1-dioxo-1λ⁶-[1,2,4]thiadiazinan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

Preferred are also compounds wherein R¹, R⁴ and R⁵ have the definitionsas describe above and R² and R³ are other than di-CF₃. Examples of suchcompounds are

-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide    and-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

A preferred group of compounds of formula I are compounds wherein R⁴ andR⁵ form together with the N-atom to which they are attached a ring with—(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″,

-   wherein R′ and R″ are as described above or may form together with    the N-atom to which they are attached a ring with —(CH₂)_(e), or by    —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,    —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,    —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,    —(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″.

Preferred from this group are those compounds wherein R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(c)—NR′—(CH₂)₂—, and wherein R′ on the N-atom is hydrogen, loweralkyl, C(O)H, C(O)CH₃, C(O)-cyclopropyl, S(O)₂-alkyl, S(O)₂—CH₂Cl orS(O)₂—N(CH₃)₂. Examples of such compounds are

-   N-[6-(4-acetyl-piperazin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(4-acetyl-[1,4]diazepan-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-oxo-[1,4]diazepan-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-imidazolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(3-acetyl-imidazolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-chloromethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-dimethylsulfamoyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2RS,5SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,6R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,6-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-formyl-2-hydroxymethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-cyclopropanecarbonyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(4-acetyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-hydroxymethyl-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide    and-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

The following compounds of formulas IA to IJ, are novel.

Encompassed by formula I are compounds of formula IA

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently    -   hydrogen,    -   —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH, or        —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each        carbon atom may be the same or different from each other and are        hydrogen    -   or C_(b)-alkyl;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl,-   R″ is hydrogen or alkyl;-   a is 0 or 1;-   b is 1 or 2; and-   d is 0, 1, 2 or 3;    or a pharmaceutically active acid-addition salt thereof.

Some specific compounds of formula IA are

-   N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[ethyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-propyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[butyl-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2,3-dihydroxy-propyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(1-hydroxymethyl-3-methyl-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-2-methyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-{6-[bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[(2-hydroxy-ethyl)-propyl-amino]-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-propyl)-amino]-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-propyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-[bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[hexyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-pentyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-1-hydroxymethyl-ethyl)-methyl-amino]-pyridin-3-yl]-N-methyl-isobutyramide.

Other compounds of formula I are compounds of formula IB

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ are each independently hydrogen, —(CH₂)₂SCH₃,    —(CH₂)₂S(O)₂CH₃, —(CH₂)₂S(O)₂NHCH₃, —(CH₂)₂NH₂, —(CH₂)₂NHS(O)₂CH₃ or    —(CH₂)₂NHC(O)CH₃;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2; and-   d is 0, 1, 2, or 3;    or a pharmaceutically active acid-addition salt thereof.

Some specific compounds of formula IB are

-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylamino-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and    2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfamoyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

Also encompassed by formula I are compounds of formula IC

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ is hydrogen;-   R⁵ is —(CH₂)_(o)-cycloalkyl, unsubstituted or substituted by    hydroxy;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2; and-   d is 0, 1, 2, or 3;    or a pharmaceutically active acid-addition salt thereof.

Some compounds of formula IC aretrans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,

-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1RS,2RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (1S,2S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

Other compounds encompassed by formula I are compounds of formula ID

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with —(CH₂)_(e)—, which is unsubstituted or substituted by one    or more substituents selected from the group consisting of    —(CR′R″)_(d)OH;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2;-   d is 0, 1, 2, or 3; and-   e is 3, 4, or 5;    or a pharmaceutically active acid-addition salt thereof.

Examples of compounds of formula ID are

wherein the compounds are selected from the group consisting of

-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide,-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-difluoro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-difluoro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide,-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide,-   (S)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3-chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2R,5R)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-dimethylamino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,5-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-4-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-amino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methylsulfanyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methanesulfonyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-2-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-4-yl]-benzamide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-cyano-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-difluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide    and-   (2S,4R)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide.

Specific compounds of formula ID, encompassed by formula I, which ringis substituted by one to three substituents, selected from the groupconsisting of —NR′R″, —(CH₂)_(d)—C(O)-lower alkyl, —CH₂OH,—(CH₂)_(d)-pyrrolidinyl, —(CH₂)_(d)—S(O)₂-alkyl, ═O, halogen or—(CH₂)_(d)OC(O)NR′R″, are the followings

-   (2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (RS)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-methanesulfonyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (R)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide,-   (S)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-N-[6-[3-(acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-[2-(acetylamino-methyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide    or-   (S)-dimethyl-carbamic acid    1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-pyrrolidin-2-ylmethyl    ester.-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[4-amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   N-[4-acetylamino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-azetidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,5-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3S,5R)-5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (2RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-2-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide,-   (3RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide,-   (3RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide    and-   (2RS,3RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

Other compounds of formula I are specific compounds of formula IE

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or    substituted    -   by one or more substituents selected from the group consisting        of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein        R′ and R″ may form together with the N-atom to which they are        attached a ring with —(CH₂)_(e),    -   or    -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,        —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,        —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3; and-   e is 3, 4, or 5;    or a pharmaceutically active acid-addition salt thereof.

Examples of compounds of formula IE are

-   N-[6-(4-acetyl-piperazin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(4-acetyl-[1,4]diazepan-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-oxo-[1,4]diazepan-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-imidazolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   N-[6-(3-acetyl-imidazolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-chloromethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-dimethylsulfamoyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2RS,5SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,6R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,6-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (3S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-formyl-2-hydroxymethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-cyclopropanecarbonyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-N-[6-(4-acetyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-ethyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-hydroxymethyl-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide    and-   2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

Additional compounds of formula I are compounds of formula IF

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl,    -   or is heteroaryl selected from the group consisting of        pyridin-2- or 3-yl, imidazolyl and oxazolyl, each of which is        unsubstituted or substituted by alkyl, halogen or alkoxy;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃; and-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with    -   —(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted        -   by one or more substituent selected from the group            consisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O,            —NR′R″, wherein R′ and R″ may form together with the N-atom            to which they are attached a ring with —(CH₂)_(e),        -   or        -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,            —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,            —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinyl or            —C(O)NR′R″;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, or 3; and-   e is 3, 4, or 5;    or a pharmaceutically active acid-addition salt thereof.

Compounds of formula IF include

-   (R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (R)-(2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide.

Formula I also encompasses compounds of formula IG I

wherein

-   R¹ is phenyl, unsubstituted or substituted by one or more    substituents selected from the group consisting of alkyl, alkoxy,    halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,    —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   R⁴ and R⁵ form together with the N-atom to which they are attached a    ring with —(CH₂)C—S(O)_(f)—(CH₂)₂—, which is unsubstituted or    substituted    -   by one or more substituents selected from the group consisting        of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein        R′ and R″ may form together with the N-atom to which they are        attached a ring with —(CH₂)_(d),    -   or    -   by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,        —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,        —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″;-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl;-   R″ is hydrogen or alkyl;-   b is 1 or 2;-   c is 1, 2, or 3;-   d is 0, 1, 2, 3 or 4; and-   e is 3, 4, or 5; and-   f is 0, 1, or 2;    or a pharmaceutically active acid-addition salt thereof.

Examples of compounds of formula IG include

-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiazolidin-3-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1RS,4RS)- or    (1RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    (Diastereomeric racemate of Example 349),-   (1RS,4SR)- or    (1RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide    (Diastereomeric racemate of Example 348),-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1,1-dioxo-1λ⁶-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (+)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (−)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,-   (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[3,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,3]thiazinan-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

The invention relates also to compounds of formula I, wherein R¹ isunsubstituted or substituted phenyl as described above and R⁴ and R⁵form together with the N-atom to which they are attached a ring with—CH₂CH═CH—CH₂—, which is unsubstituted or mono-substituted by—(CR′R″)_(d)OH. An example of such a compound is

-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

Other compounds of formula I are compounds of formula IH

wherein

-   R¹ is heteroaryl selected from the group consisting of pyridin-2- or    3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or    substituted by alkyl, halogen or alkoxy;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;    and the other substituents are as described in formula I above.

Examples for compounds of formula IH are

-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(3,5-dimethyl-isoxazol-4-yl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2,6-dimethoxy-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   N-{6′-[bis-(2-hydroxy-ethyl)-amino]-2-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide,-   (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide,-   N-{6′-[bis-(2-hydroxy-ethyl)-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide    and-   2-(3,5-bis-trifluoromethyl-phenyl)-N-{6′-[(2-hydroxy-ethyl)-methyl-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-N-methyl-isobutyramide.

Also encompassed by formula I are compounds of compounds of formula I J,

wherein

-   R¹ is aryl, unsubstituted or substituted by one or more substituents    selected from the group consisting of alkyl, alkoxy, halogen,    —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl, —C(O)NR′R″,    —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl,    -   or is heteroaryl, selected from the group consisting of        pyridin-2- or 3-yl, imidazolyl and oxazolyl, each of which is        unsubstituted or substituted by alkyl, halogen or alkoxy;-   R² and R³ are each independently hydrogen, halogen, alkyl, alkoxy,    OCHF₂, OCH₂F, OCF₃ or CF₃;-   —NR⁴R⁵ are

-   R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,    —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,    —S-alkyl or —S(O)₂—N-di-alkyl,-   R″ is hydrogen or alkyl;-   b is 1 or 2;-   d is 0, 1, 2, or 3; and-   f is 0, 1, or 2;    or a pharmaceutically active acid-addition salt thereof.

Examples of such compounds are

-   (1S,3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (rac)-(1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfinyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-dioxo-1-oxa-4λ⁶-thia-8-aza-spiro[4.5]dec-8-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-5-thia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(5,5-dioxo-1-oxa-5λ⁶-thia-9-aza-spiro[5.5]undec-9-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,4,4-tetraoxo-λ⁶,4λ⁶-dithia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,5,5-tetraoxo-1λ⁶,5λ⁶-dithia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide,-   2-(3,5-bis-trifluoromethyl-phenyl)-N-[(1S,5R)-4-(4-fluoro-2-methyl-phenyl)-6-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(8,8-dioxo-8λ⁶-thia-3-aza-bicyclo[3.2.1]oct-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,-   (1S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-((1S,4S)-5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-3-yl]-N-methyl-isobutyramide    and-   (1R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(8-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, described in schemes1 to 14 and in specific examples 1 to 421 and, for example, by a processdescribed below, which process comprises

a) reacting a compound of formula

with a compound of formula

NHR⁴R⁵  III

to produce a compound of formula

wherein R¹, R², R³, R⁴ and R⁵ have the significances given above,orb) reacting a compound of formula

with a compound of formula

to produce a compound of formula

wherein R¹, R², R³, R⁴ and R⁵ have the significances given above, andif desired, modifying one or more substituents R¹-R⁵ within thedefinitions given above, andif desired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.

In general, the compounds of formula I may be prepared as follows:

a) To a solution of a compound of formula II, for exampleN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand an amine of formula III, for example L-prolinol in dimethylsulfoxide, Na₂CO₃ or K₂CO₃ is added, and the solution is stirred at120-150° C. for about 22 h. After cooling to ambient temperature, thesolution is worked up in conventional manner orb) A mixture of a compound of formula IV, 2-chlorophenylboronic acid,palladium(II) acetate, triphenylphosphine, sodium carbonate anddimethoxyethane is heated at about 80° C. for 90 min. Then the reactionmixture is cooled to room temperature, worked up and purified.

The salt formation is effected at room temperature in accordance withmethods which are known per se and which are familiar to any personskilled in the art. Not only salts with inorganic acids, but also saltswith organic acids come into consideration. Hydrochlorides,hydrobromides, sulphates, nitrates, citrates, acetates, maleates,succinates, methan-sulphonates, p-toluenesulphonates and the like areexamples of such salts.

The following schemes 1-14 describe the processes for preparation ofcompounds of formula I in more detail. The starting materials are knowncompounds, described in EP 1035115, WO 02/08232 or WO 02/16324, or theymay be prepared according to methods known in the art. Furthermore, thepreparation of intermediates 1, 2, 3A-3L, 4A-4L and 5A-5I are describedin more detail in the experimental part.

In the schemes the following abbreviations have been used:

DMF N,N-dimethylformamide TFA trifluoroacetic acid DME ethylene glycoldimethyl ether KHMDS potassium hexamethyldisilazide DMSO di-methylsulfoxide TBDMS tert-butyldimethylsilyl-protecting group THFtetrahydrofuran Oxone potassium peroxymonosulfate DEAD diethylazodicarboxylate DIAD diisopropyl azodicarboxylate DMAP4-(N,N-dimethylamine)pyridine RT room temperature DBU1,8-diazabicyclo[5.4.0]undec-7-ene MW microwave MCPBA 3-chloroperbenzoicacid

wherein R¹, R², R³, R⁴ and R⁵ have the meaning as described above.

wherein R¹, R², R⁴ and R⁵ have the meaning as described above.

wherein R¹, R², R³, R⁴ and R⁵ have the meaning as described above.

wherein R¹, R², R³ and R⁵ have the meaning as described above.

wherein R¹, R² and R³, have the meaning as described above.

wherein R¹, R² and R³ have the meaning as described above.

Method 7

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by

reacting a compound of formula

wherein R⁴ or R⁵ contain an —OH substituent to form a compound offormula I in which the absolute configuration at the carbon center, towhich the —OH group is attached, is reversed. This is effected byreacting the compound of formula I wherein R⁴ or R⁵ contain an —OHsubstituent with triphenylphosphine, diethyl or diisopropylazodicarboxylate and benzoic acid in THF followed by treatment withsodium methylate or sodium hydroxide in methanol.

wherein R¹, R² and R³ have the meaning as described above.

wherein n, R¹, R² and R³ have the meaning as described above.

wherein R¹, R² and R³ have the meaning as described above.

Method 15

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by

reacting a compound of formula

wherein R⁴ or R⁵ contain an —OH substituent to form a compound offormula I in which the —OH group has been transformed into an —S-alkyl,—S(O)-alkyl or S(O)₂-alkyl group under inversion of the absoluteconfiguration at the carbon center to which the —OH group has beenattached using the following procedure:

The —OH group is first transformed into a —OS(O)₂CH₃ group by reactionwith methanesulfonyl chloride and triethylamine in dichloromethane. Bytreatment with the salt of a thioalkane such as sodium methanethiolatein methanol or DMF the —OS(O)₂CH₃ group is further transformed into the—S-alkyl group. The —S-alkyl group can be oxidized to an —S(O)-alkylgroup by treatment with Oxone in methanol or MCPBA in dichloromethane.The compounds of formula I containing an —S(O)-alkyl group can beisolated or oxidized further without isolation to compounds containingan —S(O)₂-alkyl group by treatment with Oxone in methanol or MCPBA indichloromethane (Examples 331 and 388).

Method 16

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by

reacting a compound of formula

wherein R⁴ or R⁵ contain an —OH substituent to form a compound offormula I in which the —OH group has been transformed into an—S(O)₂—NR′R″ group under inversion of the absolute configuration at thecarbon center to which the —OH group has been attached using thefollowing procedure:

The —OH group is transformed into a —SC(O)CH₃ group by reaction withtriphenylphosphine, diethyl azodicarboxylate and thioacetic acid in THF.The —SC(O)CH₃ group is oxidized to an —SO₃H group by reaction with anaqueous solution of hydrogen peroxide in acetic acid. Compoundscontaining the —SO₃H are treated consecutively with oxalyl chloride anda catalytic amount of DMF in dichloromethane and an amine to formcompounds of formula I wherein R⁴ or R⁵ contain an —S(O)₂—NR′R″ group.

As mentioned earlier, the compounds of formula I and theirpharmaceutically usable addition salts possess valuable pharmacologicalproperties. It has been found that the compounds of the presentinvention are dual antagonists of the Neurokinin 1 and 3 receptors.

The compounds were investigated in accordance with the tests givenhereinafter.

NK₁

The affinity of test compounds for the NK₁ receptor was evaluated athuman NK₁ receptors in CHO cells infected with the human NK₁ receptor(using the Semliki virus expression system) and radiolabelled with[³H]substance P (final concentration 0.6 nM). Binding assays wereperformed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%)leupeptin (16.8 μg/ml), MnCl₂ (3 mM) and phosphoramidon (2 μM). Bindingassays consisted of 250 μl of membrane suspension (approximately 1.5μg/well in a 96 well plate), 0.125 μl of buffer of displacing agent and125 μl of [³H]substance P. Displacement curves were determined with atleast seven concentrations of the compound. The assay tubes wereincubated for 60 min at room temperature after which time the tubecontents were rapidly filtered under vacuum through GF/C filterspresoaked for 60 min with PEI (0.3%) with 3×1 ml washes of HEPES buffer(50 mM, pH 7.4). The radioactivity retained on the filters was measuredby scintillation counting. All assays were performed in duplicate in atleast 2 separate experiments.

NK₃

Recombinant human NK₃ (hNK₃) receptor affinity was determined in a 96well plate assay, using [³H]SR142801 (final concentration 0.3 nM) toradiolabel the hNK₃ receptor in the presence of 10 concentrations ofcompeting compound or buffer. Non specific binding was determined using10 μM SB222200. Assay buffer consisted of Tris-HCl (50 mM, pH 7.4), BSA(0.1%), MnCl₂ (4 mM) and phosphoramidon (1 μM). Membrane preparations ofhNK3 receptors (approximately 2.5 μg/well in a 96 well plate) were usedto initiate the incubation for 90 min at room temperature. This assaywas terminated by rapid filtration under vacuum through GF/C filters,presoaked for 90 min with PEI (0.3%), with 3×0.5 ml washes of ice-coldTris buffer (50 mM, pH 7.4) containing 0.1% BSA. The radioactivityretained on the filters was measured by scintillation counting. Allassays were performed in duplicate in at least two separate experiments.

The activity of the present compounds is described in the table below:

Subst. on pKi R¹ R²/R³ R⁴ R⁵ R¹ NK1/NK3 Expl. 2-Cl 3,5-di Cl —(CH₂)₂OH Hphenyl 8.56/8.05 1 2-Cl 3,5-di Cl

phenyl 8.47/9.05 2 2-Cl 3,5-di Cl

phenyl 8.85/9.06 3 2-Cl 3-F/5-CF₃

phenyl 8.35/8.81 4 2-Cl 3-F/5-CF₃

phenyl 8.81/8.76 5 2-Cl 3,5-di-F

phenyl 8.14/8.31 6 2-Cl 3-OCH₃/5-Cl

phenyl 8.32/8.75 7 2-Cl 3-OCH₃/5-Cl

phenyl 8.77/8.90 8 2-Cl 3,5-di-CH₃

phenyl 8.19/8.44 9 2-Cl 3,5-di-CH₃

phenyl 8.67/8.44 10 2-CH₃ 3,5-di-Cl

phenyl 8.75/8.96 11 2-CH₃ 3,5-di-Cl

phenyl 8.95/8.86 12 2-CH₃ 3-CF₃/5-F

phenyl 8.66/8.81 13 2-CH₃ 3-F/5-CF₃

phenyl 8.89/8.52 14 2-CH₃ 3,5-di-F

phenyl 8.20/8.35 15 2-CH₃ 3,5-di-F

phenyl 8.58/8.39 16 2-CH₃ 3-OCH₃/5-Cl

phenyl 8.41/8.50 17 2-CH₃ 3-OCH₃/5-Cl

phenyl 8.93/8.60 18 2-CH₃ 3,5-di-CH₃

phenyl 8.53/8.29 19 2-CH₃ 3,5-di-CH₃

phenyl 8.94/8.21 20 2-CH₃/4-F 3,5-di-Cl —(CH₂)₂OH H phenyl 8.89/8.06 212-CH₃/4-F 3,5-di-Cl

phenyl 8.29/8.93 22 2-CH₃/4-F 3,5-di-Cl

phenyl 9.05/8.80 23 2-CH₃/4-F 3-CF₃/5-F

phenyl 8.88/9.05 24 2-CH₃/4-F 3-CF₃/5-F

phenyl 9.03/8.76 25 2-CH₃/4-F H/5-CF₃

phenyl 8.52/8.24 26 2-CH₃/4-F H/5-CF₃

phenyl 8.82/7.97 27 2-CH₃/4-F 3,5-di-F

phenyl 8.55/8.40 28 2-CH₃/4-F 3,5-di-F

phenyl 8.81/8.45 29 2-CH₃/4-F 3-OCH₃/5-Cl

phenyl 8.43/8.45 30 2-CH₃/4-F 3-OCH₃/5-Cl

phenyl 9.01/8.78 31 2-CH₃/4-F 3,5-di-CH₃

phenyl 8.51/8.52 32 2-CH₃/4-F 3,5-di-CH₃

phenyl 8.93/8.52 33 2-Cl 3-OCHF₂/5-Cl

phenyl 8.41/9.08 34 2-Cl 3-OCHF₂/5-Cl

phenyl 8.71/9.26 35 2-CH₃ 3-OCHF₂/5-Cl

phenyl 8.37/9.15 36 2-CH₃ 3-OCHF₂/5-Cl

phenyl 8.92/9.21 37 2-CH₃/4-F 3-OCHF₂/5-Cl

phenyl 8.45/8.65 38 2-CH₃/4-F 3-OCHF₂/5-Cl

phenyl 8.98/8.89 39 2-Cl 3,5-di-CF₃

phenyl 9.19/8.99 40 2-Cl 3,5-di-CF₃

phenyl 8.97/8.12 41 2-Cl 3,5-di-CF₃

phenyl 8.78/9.08 42 2-Cl 3,5-di-CF₃

phenyl 8.62/7.45 43 2-Cl 3,5-di-CF₃

phenyl 9.20/7.81 44 2-Cl 3,5-di-CF₃

phenyl 8.64/8.70 45 2-Cl 3,5-di-CF₃

phenyl 9.22/8.06 46 2-Cl 3,5-di-CF₃

phenyl 8.71/8.20 47 2-Cl 3,5-di-CF₃

phenyl 9.27/8.06 48 2-Cl 3,5-di-CF₃

phenyl 9.32/7.83 49 2-Cl 3,5-di-CF₃

phenyl 8.85/7.84 50 2-Cl 3,5-di-CF₃

phenyl 9.19/7.54 51 2-Cl 3,5-di-CF₃

phenyl 8.96/8.10 52 2-Cl 3,5-di-CF₃

phenyl 8.60/7.61 53 2-Cl 3,5-di-CF₃ —(CH₂)₂OH —CH₃ phenyl 9.00/8.57 542-Cl 3,5-di-CF₃ —(CH₂)₂OH —CH₂CH₃ phenyl 8.48/7.95 55 2-Cl 3,5-di-CF₃—(CH₂)₂OH —(CH₂)₂CH₃ phenyl 8.34/8.28 56 2-Cl 3,5-di-CF₃ —(CH₂)₂OH—(CH₂)₂CH₃ phenyl 8.00/7.56 57 2-Cl 3,5-di-CF₃ —CH₂CH(OH)CH₂OH CH₃phenyl 8.62/8.24 58 2-Cl 3,5-di-CF₃ CH(CH₂OH)CH₂CH(CH₃)₂ H phenyl8.49/8.31 59 2-Cl 3,5-di-CF₃

H phenyl 8.90/8.10 60 2-Cl 3,5-di-CF₃

phenyl 9.38/7.85 61 2-Cl 3,5-di-CF₃

phenyl 8.99/8.18 62 2-Cl 3,5-di-CF₃

phenyl 8.74/8.93 63 2-Cl 3,5-di-CF₃

phenyl 9.00/8.54 64 2-Cl 3,5-di-CF₃

phenyl 8.94/8.56 65 2-Cl 3,5-di-CF₃

phenyl 8.83/8.89 66 2-Cl 3,5-di-CF₃ —(CH₂)₂OH H phenyl 9.14/7.94 672-CH₃/4-F 3,5-di-CF₃ —(CH₂)₂OH H phenyl 8.84/8.49 68 2-Cl/4-F 3,5-di-CF₃—(CH₂)₂OH H phenyl 8.95/7.84 69 2-Cl/4-Cl 3,5-di-CF₃ —(CH₂)₂OH H phenyl8.70/8.39 70 2-Cl/4-Cl 3,5-di-CF₃

H phenyl 8.69/8.04 71 2-Cl 3,5-di-CF₃

H phenyl 9.14/7.58 72 2-Cl 3,5-di-CF₃

H phenyl 9.06/8.13 73 2-Cl 3,5-di-CF₃

H phenyl 9.06/8.24 74 2-Cl 3,5-di-CF₃

H phenyl 8.77/7.91 75 2-Cl 3,5-di-CF₃

H phenyl 8.80/7.97 76 2-CH₃/4-F 3,5-di-CF₃

H phenyl 9.19/8.32 77 2-Cl 3,5-di-CF₃

H phenyl 8.55/8.21 78 2-Cl 3,5-di-CF₃

H phenyl 8.87/7.98 79 2-Cl 3,5-di-CF₃

H phenyl 8.90/8.05 80 2-Cl 3,5-di-CF₃

H phenyl 8.68/8.25 81 2-Cl 3,5-di-CF₃

phenyl 9.03/9.09 82 2-CH₃ 3,5-di-CF₃

phenyl 8.93/8.96 83 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.47/8.76 84 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.63/8.64 85 2-Cl/4-Cl 3,5-di-CF₃

phenyl 8.78/8.45 86 3-Cl/4-Cl 3,5-di-CF₃

phenyl 8.80/8.02 87 4-F 3,5-di-CF₃

phenyl 8.87/8.03 88 2-Cl 3,5-di-CF₃

H phenyl 9.31/8.49 89 2-Cl 3,5-di-CF₃

H phenyl 8.75/8.22 90 2-Cl/4-Cl 3,5-di-CF₃

H phenyl 8.61/8.25 91 2-CH₃/4-F 3,5-di-CF₃

H phenyl 8.99/7.67 92 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.95/8.13 93 2-Cl/4-Cl 3,5-di-CF₃

phenyl 8.37/7.83 94 3-Cl/4-Cl 3,5-di-CF₃

phenyl 8.42/8.03 95 2-Cl 3,5-di-CF₃

phenyl 8.16/7.84 96 2-Cl 3,5-di-CF₃

phenyl 9.13/8.89 97 2-Cl 3,5-di-CF₃

phenyl 9.16/8.46 98 2-CH₃/4-F 3,5-di-CF₃

phenyl 9.09/7.26 99 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.74/7.70 100 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.77/8.03 101 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.71/7.88 102 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.78/7.80 103 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.79/8.17 104 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.99/8.28 105 2-CH₃/4-F 3,5-di-CF₃

phenyl 9.23/8.33 106 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.63/7.93 107 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.61/8.05 108 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.69/7.87 109 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.58/7.86 110 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.68/8.39 111 2-Cl 3,5-di-CF₃

phenyl 9.25/8.26 112 2-Cl 3,5-di-CF₃

phenyl 8.24/8.46 113 2-CH₃/4-F 3,5-di-CF₃

phenyl 9.22/7.79 114 4-F 3,5-di-CF₃ —(CH₂)₂OH CH₃ phenyl 8.73/7.52 1154-F 3,5-di-CF₃ —(CH₂)₂OH CH₂CH₃ phenyl 8.41/7.49 116 2-CH₃ 3,5-di-CF₃—(CH₂)₂OH CH₃ phenyl 8.68/8.51 117 2-CH₃ 3,5-di-CF₃ —(CH₂)₂OH CH₂CH₃phenyl 8.44/8.34 118 2-CH₃ 3,5-di-CF₃ —(CH₂)₂OH CH₂CH₂CH₃ phenyl8.40/8.64 119 2-CH₃ 3,5-di-CF₃

H phenyl 8.86/8.00 120 2-CH₃ 3,5-di-CF₃

phenyl 8.54/7.96 121 2-CH₃ 3,5-di-CF₃

H phenyl 8.72/7.71 122 2-CH₃ 3,5-di-CF₃

H phenyl 8.60/7.90 123 2-Cl 3,5-di-CF₃

phenyl 8.58/7.86 124 2-Cl 3,5-di-CF₃

H phenyl 8.55/7.86 125 2-Cl 3,5-di-CF₃

H phenyl 8.60/8.11 126 2-CH₃/3-F 3,5-di-CF₃

phenyl 8.66/8.82 127 2-CH₃/5-F 3,5-di-CF₃

phenyl 8.58/8.25 128 2-Br 3,5- di-CF₃

phenyl 9.07/8.58 129 2-Br 3,5-di-CF₃

phenyl 8.78/8.64 130 2-Br 3,5-di-CF₃

H phenyl 8.97/8.37 131 2-Br 3,5-di-CF₃

H phenyl 8.88/8.14 132 2-Br 3,5-di-CF₃

phenyl 9.10/8.70 133 2-Br 3,5-di-CF₃

phenyl 8.65/8.66 134 3,4-di-Cl 3,5-di-CF₃

phenyl 8.37/7.50 135 2,4-di-Cl 3,5-di-CF₃

phenyl 8.79/8.84 136 2,4-di-Cl 3,5-di-CF₃

phenyl 8.55/8.87 137 2-Cl 3,5-di-CF₃

phenyl 8.78/9.00 138 2-Cl 3,5-di-CF₃

phenyl 9.17/7.90 139 2-Cl 3,5-di-CF₃

phenyl 9.11/8.83 140 2-Cl 3,5-di-CF₃

phenyl 8.19/7.73 141 2-CH₃/4-F 3,5-di-CF₃

H phenyl 8.89/8.59 142 2-CH₃ 3,5-di-CF₃

H phenyl 8.52/8.44 143 2-Cl 3,5-di-CF₃

H phenyl 8.44/8.92 144 2-Cl 3,5-di-CF₃

H phenyl 9.08/8.10 145 2-Cl 3,5-di-CF₃

H phenyl 9.05/7.93 146 2-Cl 3,5-di-CF₃

H phenyl 9.14/7.98 147 2-Cl 3,5-di-CF₃ (CH₂)₂OH (CH₂)₅CH₃ phenyl8.68/7.92 148 2-Cl 3,5-di-CF₃ (CH₂)₂OH (CH₂)₅CH₃ phenyl 8.89/8.21 1492-Cl 3,5-di-CF₃ (CH₂)₃OH (CH₂)₂OH phenyl 8.88/9.01 150 2-Cl 3,5-di-CF₃

H phenyl 8.94/7.56 151 2-Cl 3,5-di-CF₃

H phenyl 9.12/8.11 152 2-Cl 3,5-di-CF₃

H phenyl 9.31/8.39 153 2-CH₃/4-F 3,5-di-CF₃

H phenyl 8.50/8.24 154 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.76/9.06 155 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.76/8.80 156 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.60/8.80 157 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.78/9.02 158 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.75/8.02 159 2-Cl 3,5-di-CF₃

phenyl 8.69/7.52 160 2-Cl 3,5-di-CF₃

phenyl 7.94/8.17 161 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.68/7.73 162 2-CH₃ 3,5-di-CF₃

phenyl 8.74/7.55 163 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.79/7.80 164 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.68/8.96 165 2-CH₃/5-F 3,5-di-CF₃

phenyl 8.42/8.92 166 2-CH₃/3-F 3,5-di-CF₃

phenyl 8.35/9.01 167 2-CH₃ 3,5-di-CF₃

phenyl 8.68/8.00 168 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.85/7.67 169 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.71/8.04 170 2-Cl 3,5-di-CF₃

phenyl 8.43/7.61 171 2-CH₃ 3,5-di-CF₃

phenyl 8.15/7.89 172 2-CH₃ 3,5-di-CF₃

H phenyl 8.72/8.73 173 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.78/8.59 174 2-CH₃ 3,5-di-CF₃

phenyl 8.79/8.67 175 2-CH₃ 3,5-di-CF₃

phenyl 8.68/7.58 176 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.92/8.58 177 2-CH₃ 3,5-di-CF₃

phenyl 9.03/8.46 178 2-CH₃ 3,5-di-CF₃

phenyl 8.82/8.39 179 2-Cl 3,5-di-CF₃

phenyl 8.79/8.49 180 2-Cl 3,5-di-CF₃

phenyl 8.70/8.47 181 2-Cl 3,5-di-CF₃

phenyl 9.03/7.49 182 2-CH₃ 3,5-di-CF₃

phenyl 8.96/7.57 183 2-CH₃ 3,5-di-CF₃

phenyl 8.91/7.70 184 2-CH₃ 3,5-di-CF₃

phenyl 8.81/7.49 185 2-CH₃ 3,5-di-CF₃

phenyl 8.85/7.91 186 2-Cl 3,5-di-CF₃

phenyl 8.78/7.59 187 2-Cl 3,5-di-CF₃

phenyl 8.88/7.81 188 2-Cl 3,5-di-CF₃

phenyl 8.82/8.40 189 2-CH₃ 3,5-di-CF₃

phenyl 8.80/8.39 190 2-CH₃ 3,5-di-CF₃

phenyl 8.69/7.61 191 2-CH₃ 3,5-di-CF₃

phenyl 8.52/7.46 192 2-Cl 3,5-di-CF₃

phenyl 8.84/7.92 193 2-Cl 3,5-di-CF₃

phenyl 8.78/7.76 194 2-Cl 3,5-di-CF₃

phenyl 8.74/7.54 195 2-CH₃/4-F 3,5-di-CF₃

CH₃ phenyl 8.76/8.34 196 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.54/8.41 197 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.75/8.96 198 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.60/7.81 199 4-CH₃ 3,5-di-CF₃

phenyl 8.63/7.74 200 — 3,5-di-CF₃

phenyl 8.83/8.06 201 4-F 3,5-di-CF₃

phenyl 8.92/8.13 202 4-Cl 3,5-di-CF₃

phenyl 8.69/7.98 203 4-N(CH₃)₂ 3,5-di-CF₃

phenyl 7.82/7.83 204 3-Br 3,5-di-CF₃

phenyl 8.71/8.07 205 3-Cl 3,5-di-CF₃

phenyl 8.73/7.80 206 3-F 3,5-di-CF₃

phenyl 8.86/8.33 207 3,5-di-F 3,5-di-CF₃

phenyl 8.87/8.21 208 3,4-di-F 3,5-di-CF₃

phenyl 8.87/8.46 209 3-F/4-CH₃ 3,5-di-CF₃

phenyl 8.64/7.86 210 3-CH₃/4-F 3,5-di-CF₃

phenyl 8.78/7.81 211 3-Cl/4-F 3,5-di-CF₃

phenyl 9.09/8.60 212 2-NH₂ 3,5-di-CF₃

phenyl 9.18/8.49 213 2-OCH₃ 3,5-di-CF₃

phenyl 8.99/8.56 214 2-OH 3,5-di-CF₃

phenyl 8.99/8.35 215 2-CH₃ 3,5-di-CF₃

phenyl 8.87/9.10 216 2-SCH₃ 3,5-di-CF₃

phenyl 8.98/8.62 217 2-SO₂CH₃ 3,5-di-CF₃

phenyl 8.58/8.14 218 2 -CONH₂ 3,5-di-CF₃

phenyl 8.84/7.69 219 2,4-di-F 3,5-di-CF₃

phenyl 8.82/8.18 220 2-Cl/4-F 3,5-di-CF₃

phenyl 9.03/8.28 221 2-CHO/4-F 3,5-di-CF₃

phenyl 8.98/8.99 222 2-CH₂OH/4-F 3,5-di-CF₃

phenyl 9.15/8.51 223 2-CHO 3,5-di-CF₃

phenyl 8.95/8.82 224 2-CH₂OH 3,5-di-CF₃

phenyl 8.78/8.59 225 2,5-di-Cl 3,5-di-CF₃

phenyl 8.11/7.78 226 2-CH₃/5-F 3,5-di-CF₃

phenyl 8.96/8.86 227 2-CH₃/3-F 3,5-di-CF₃

phenyl 8.93/8.85 228 2,3-di-Cl 3,5-di-CF₃

phenyl 8.53/8.73 229 3,5-di-CH₃ 3,5-di-CF₃

Isoxazol-4-yl 9.13/8.57 230 2,4-di-OCH₃ 3,5-di-CF₃

Pyridin-3-yl 8.61/7.85 231 2-Cl 3,5-di-CF₃

Pyridin-3-yl 9.24/8.87 232 2-CH₃ 3,5-di-CF₃

Pyridin-3-yl 9.37/8.41 233 3-Cl 3,5-di-CF₃

Pyridin-2-yl 8.66/7.96 234 2-Cl/4-F 3,5-di-CF₃

phenyl 8.78/8.90 235 2,4-di-Cl 3,5-di-CF₃

phenyl 8.75/8.75 236 2,4-di-F 3,5-di-CF₃

phenyl 8.99/8.11 237 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.91/8.99 238 2-CHO/4-F 3,5-di-CF₃

phenyl 8.79/8.83 239 2-CH₂OH/4-F 3,5-di-CF₃

phenyl 9.10/8.52 240 2-CH₃ 3,5-di-CF₃

phenyl 8.84/8.79 241 2-F 3,5-di-CF₃

phenyl 8.88/8.16 242 2-CF₃ 3,5-di-CF₃

phenyl 8.41/8.33 243 2-OCH₃ 3,5-di-CF₃

phenyl 9.00/8.15 244 2-CN 3,5-di-CF₃

phenyl 8.92/8.96 245 2-Br 3,5-di-CF₃

phenyl 8.72/8.83 246 — 3,5-di-CF₃

phenyl 8.82/7.80 247 3-CH₃/4-F 3,5-di-CF₃

phenyl 8.66/7.56 248 2-CH₃/3-F 3,5-di-CF₃

phenyl 8.70/8.99 249 2-CH₃/5-F 3,5-di-CF₃

phenyl 8.71/8.70 250 3-F 3,5-di-CF₃

phenyl 8.88/8.05 251 3,4-di-Cl 3,5-di-CF₃

phenyl 8.78/8.21 252 2,3-di-Cl 3,5-di-CF₃

phenyl 8.54/8.50 253 2-Cl 3,5-di-CF₃

Pyridin-3-yl 9.01/8.51 254 2-CH₃ 3,5-di-CF₃

Pyridin-3-yl 9.02/7.97 255 6-Cl 3,5-di-CF₃

Pyridin-2-yl 8.62/7.70 256 2CH₃ 3,5-di-CF₃

phenyl 257 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.70/8.00 258 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.78/7.82 259 2-CH₃ 3,5-di-CF₃

phenyl 8.85/7.75 260 2-CH₃ 3,5-di-CF₃

phenyl 8.89/9.04 261 2-CF₃ 3,5-di-CF₃

phenyl 8.10/8.01 262 2-OCH₃ 3,5-di-CF₃

phenyl 8.99/8.87 263 2-F 3,5-di-CF₃

phenyl 8.83/8.67 264 — 3,5-di-CF₃

phenyl 8.84/8.31 265 4-F 3,5-di-CF₃

phenyl 8.92/8.42 266 4-CH₃ 3,5-di-CF₃

phenyl 8.44/7.54 267 3,4-di-Cl 3,5-di-CF₃

phenyl 8.64/8.62 268 3-Cl 3,5-di-CF₃

phenyl 8.73/8.45 269 2,5-di-Cl 3,5-di-CF₃

phenyl 8.58/8.66 270 2,3-di-Cl 3,5-di-CF₃

phenyl 8.52/8.86 271 2-Cl/4-F 3,5-di-CF₃

phenyl 8.70/8.96 272 2-CHO/4-F 3,5-di-CF₃

phenyl 8.84/8.81 273 2-CH₂OH/4-F 3,5-di-CF₃

phenyl 8.89/8.82 274 2-CH₃/3-F 3,5-di-CF₃

phenyl 8.83/9.24 275 2-CH₃/5-F 3,5-di-CF₃

phenyl 8.84/8.86 276 2,5-di-F 3,5-di-CF₃

phenyl 8.83/8.61 277 2-CH₃ 3,5-di-CF₃

Pyridin-3-yl 9.09/8.57 278 2-CH₃ 3,5-di-CF₃

phenyl 8.55/8.93 279 2-OCH₃ 3,5-di-CF₃

phenyl 8.74/8.73 280 2-Br 3,5-di-CF₃

phenyl 8.46/8.74 281 2-F 3,5-di-CF₃

phenyl 8.51/8.65 282 2,4-di-Cl 3,5-di-CF₃

phenyl 8.55/8.83 283 2,5-di-Cl 3,5-di-CF₃

phenyl 8.83/8.84 284 2,3-di-Cl 3,5-di-CF₃

phenyl 8.80/8.73 285 3,4-di-Cl 3,5-di-CF₃

phenyl 8.87/8.43 286 4-Cl 3,5-di-CF₃

phenyl 8.20/8.13 287 4-F 3,5-di-CF₃

phenyl 8.58/8.60 288 — 3,5-di-CF₃

phenyl 8.52/8.30 289 2-CH₃ 3,5-di-CF₃

Pyridin-3-yl 8.84/8.75 290 2-CH₃ 3,5-di-CF₃

Pyridin-3-yl 8.48/8.11 291 6-CH₃ 3,5-di-CF₃

Pyridin-3-yl 8.44/9.11 292 6-CH₃ 3,5-di-CF₃

Pyridin-3-yl 8.42/8.79 293 6-CH₃ 3,5-di-CF₃

CH₃ Pyridin-3-yl 8.29/8.37 294 2-CH₃ 3,5-di-CF₃

phenyl 8.81/8.78 295 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.60/8.76 296 2-CH₃ 3,5-di-CF₃

phenyl 8.54/8.88 297 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.81/915 298 2-CH₃ 3,5-di-CF₃

phenyl 8.59/8.97 299 2-CH₃/4-F 3,5-di-CF₃

phenyl 9.02/9.31 300 2-CH₃ 3,5-di-CF₃

phenyl 8.67/8.64 301 2-CH₃/4-F 3,5-di-CF₃

phenyl 8.60/7.69 302 2-CH3/4-F 3,5-di-CF3

phenyl 8.88/7.82 303 —CH3/4-F ,5-di-CF3

henyl  .77/8.73 04 —Cl/H ,5-di-CF₃

henyl  .65/8.18 05 —CH₃/H ,5-di-CF₃

henyl  .76/7.92 06 —CH₃/4-F ,5-di-CF₃

henyl  .06/7.66 07 —CH₃/4-F ,5-di-CF₃

henyl  .65/8.25 08 —CH₃/4-F ,5-di-CF₃

henyl  .67/7.88 09 —CH₃/4-F ,5-di-CF₃

henyl  .83/7.70 10 —CH₃/4-F ,5-di-CF₃

henyl  .93/7.94 11 —CH₃/4-F ,5-di-CF₃

henyl  .65/8.18 12 —CH₃/4-F ,5-di-CF₃

henyl  .93/8.32 13 —CH₃/4-F ,5-di-CF₃

henyl  .90/8.14 14 —CH₃/4-F ,5-di-CF₃

henyl  .99/8.51 15 —CH₃/4-F ,5-di-CF₃

henyl  .88/7.76 16 —CH₃/4-F ,5-di-CF₃

henyl  .97/8.40 17 —CH₃/4-F ,5-di-CF₃

henyl  .11/8.50 18 —CH₃/4-F ,5-di-CF₃

henyl  .12/8.34 19 —CH₃/4-F ,5-di-CF₃

henyl  .90/7.80 20 —CH₃/4-F ,5-di-CF₃

henyl  .81/7.98 21 —CH₃/4-F ,5-di-CF₃

henyl  .75/7.61 22 —CH₃/4-F ,5-di-CF₃

henyl  .15/8.07 23 —CH₃/4-F ,5-di-CF₃

henyl  .67/7.93 24 —CH₃/4-F ,5-di-CF₃

henyl  .05/8.05 25 —CH₃/4-F ,5-di-CF₃

henyl  .87/8.58 26 —CH₃/4-F ,5-di-CF₃

henyl  .91/7.89 27 —CH₃/4-F ,5-di-CF₃

henyl  .70/8.34 28 —CH₃/4-F ,5-di-CF₃

henyl  .63/7.70 29 —CH₃/4-F ,5-di-CF₃

henyl  .92/7.83 30 —CH₃/4-F ,5-di-CF₃

henyl  .02/8.60 31 —Cl/H ,5-di-CF₃

henyl  .70/8.04 32 —Cl/H ,5-di-CF₃

henyl  .82/8.06 33 —Cl/H ,5-di-CF₃

henyl  .01/8.56 34 —CH₃/4-F ,5-di-CF₃

henyl  .59/8.25 35 —CH₃/4-F ,5-di-CF₃

henyl  .00/8.67 36 —CH₃/4-F ,5-di-CF₃

henyl  .79/7.99 37 —CH₃/4-F ,5-di-CF₃

henyl  .05/8.74 38 —CH₃/4-F ,5-di-CF₃

henyl  .97/7.98 39 —CH₃/4-F ,5-di-CF₃

henyl  .88/7.81 40 —CH₃/4-F ,5-di-CF₃

henyl  .92/8.18 41 —CH₃/4-F ,5-di-CF₃

henyl  .65/8.93 42 —CH₃/4-F ,5-di-CF₃

henyl  .78/7.70 43 —CH₃/4-F ,5-di-CF₃

henyl  .99/7.69 44 —CH₃/4-F ,5-di-CF₃ —(CH₂)₂SCH₃ henyl  .00/7.95 45—CH₃/4-F ,5-di-CF₃ —(CH₂)₂S(O)₂CH3 henyl  .81/8.08 46 —CH₃/4-F ,5-di-CF₃

henyl  .93/7.93 47 —CH₃/4-F ,5-di-CF₃

henyl  .97/8.55 48 —CH₃/4-F ,5-di-CF₃

henyl  .85/.65 49 —CH₃/4-F ,5-di-CF₃

henyl  .80/8.31 50 —CH₃/4-F ,5-di-CF₃

henyl  .39/8.27 51 —CH₃/H ,5-di-CF₃

henyl  .07/8.33 52 —CH₃/H ,5-di-CF₃

henyl  .08/8.81 53 —CH₃/4-F ,5-di-CF₃

henyl  .65/7.70 54 —CH₃/4-F ,5-di-CF₃

henyl  .63/7.72 55 —CH₃/4-F ,5-di-CF₃

henyl  .95/7.92 56 —CH₃/4-F ,5-di-CF₃ —(CH₂)₂NH₂ henyl  .74/7.65 57—CH₃/4-F ,5-di-CF₃ —(CH₂)₂NHS(O)₂CH₃ henyl  .47/7.77 58 —CH₃/4-F,5-di-CF₃

henyl  .90/8.00 59 —CH₃/4-F ,5-di-CF₃ —(CH₂)₂NHC(O)CH₃ henyl  .78/7.8460 —CH₃/4-F ,5-di-CF₃

henyl  .42/7.89 61 —CH₃/H ,5-di-CF₃

henyl  .03/8.32 62 —Cl/H ,5-di-CF₃

henyl  .13/8.57 63 —CH₃/3-Cl ,5-di-CF₃

henyl  .15/7.78 64 —CH₃/3-F ,5-di-CF₃

henyl  .03/8.42 65 —CH₃/4-F ,5-di-CF₃

henyl  .22/8.67 66 —CH₃/4-F ,5-di-CF₃

henyl  .11/8.44 67 —CH₃/4-F ,5-di-CF₃

henyl  .98/8.39 68 —CH₃/4-F ,5-di-CF₃

henyl  .16/8.67 69 —CH₃/4-F ,5-di-CF₃

henyl  .03/8.55 70 —CH₃/4-F ,5-di-CF₃

henyl  .03/8.91 71 —Cl/H ,5-di-CF₃

henyl  .05/8.68 72 —CH₃/H ,5-di-CF₃

henyl  .16/8.80 73 —CH₃/4-F ,5-di-CF₃

henyl  .21/9.22 74 —Cl/H ,5-di-CF₃

henyl  .09/8.95 75 —CH₃/H ,5-di-CF₃

henyl  .14/9.06 76 —CH₃/4-F ,5-di-CF₃

henyl  .93/8.44 77 —CH₃/4-F ,5-di-CF₃

henyl  .24/8.76 78 —CH₃/4-F ,5-di-CF₃

henyl  .79/8.32 79 —CH₃/4-F ,5-di-CF₃

henyl  .06/8.67 80 —CH₃/4-F ,5-di-CF₃

henyl  .01/7.90 81 —CH₃/4-F ,5-di-CF₃

henyl  .07/7.96 82 —CH₃/4-F ,5-di-CF₃

henyl  .89/9.31 83 —CH₃/4-F ,5-di-CF₃

henyl  .74/8.99 84 —CH₃/4-F ,5-di-CF₃

henyl  .84/9.19 85 —CH₃/4-F ,5-di-CF₃

henyl  .77/9.18 86 —CH₃/4-F ,5-di-CF₃

henyl  .58/8.67 87 —C1/H ,5-di-CF₃ —(CH₂)₂S(O)₂NHCH₃ henyl  .65/8.04 88—Cl/H ,5-di-CF₃

henyl  .03/8.13 89 —Cl/H ,5-di-CF₃

henyl  .09/8.22 90 —CH₃/4-F ,5-di-CF₃

henyl  .85/8.26 91 —CH₃/H ,5-di-CF₃

henyl  .72/8.77 92 —CH₃/4-F ,5-di-CF₃

henyl  .79/8.90 93 —CH₃/4-F ,5-di-CF₃

henyl  .22/8.64 94 —CH₃/H ,5-di-CF₃

henyl  .12/8.31 95 —CH₂OH/H ,5-di-CF₃

henyl  .85/8.04 96 —CH₃/4-F ,5-di-CF₃

henyl  .26/8.24 97 —CH₃/H ,5-di-CF₃

henyl  .85/7.73 98 —CH₃/H ,5-di-OCH₃

henyl  .05/8.15 99 —CH₃/H ,5-di-OCH₃

henyl  .48/8.22 00 —CH₃/4-F ,5-di-OCH₃ —(CH₂)₂OH henyl  .59/7.70 01—CH₃/4-F ,5-di-OCH₃

henyl  .44/8.33 02 —CH₃/4-F ,5-di-OCH₃

henyl  .82/8.24 03 —Cl/H ,5-di-OCH₃

henyl  .40/8.28 04 —CH₃/H ,5-di-OCHF₂ —(CH₂)₂OH henyl  .72/8.30 05—CH₃/H ,5-di-OCHF₂

henyl  .98/9.04 06 —CH₃/H ,5-di-OCHF₂

henyl  .53/9.06 07 —CH₃/4-F ,5-di-OCHF₂ —(CH₂)₂OH H henyl  .71/8.25 08—CH₃/4-F ,5-di-OCHF₂

henyl  .51/8.99 09 —Cl/H ,5-di-OCHF₂

henyl  .86/9.14 10 —Cl/H ,5-di-OCHF₂

henyl  .46/9.17 11 —Cl/H ,5-di-OCHF₂ —(CH₂)₂OH henyl  .59/8.41 12—CH₃/4-F ,5-di-OCHF₂

henyl  .05/9.05 13 —CH₃/H —OCF₃

henyl  .10/8.23 14 —CH₃/4-F —OCF₃

henyl  .39/8.24 15 —Cl/H ,5-di-OCHF₂

henyl  .83/7.64 16 —CH₃/4-F ,5-di-OCHF₂

henyl  .13/7.63 17 —Cl/H ,5-di-OCHF₂

henyl  .01/8.45 18 —CH₃/4-F ,5-di-OCHF₂

henyl  .18/8.42 19 —CH₃/H ,5-di-OCHF₂

henyl  .13/8.49 20 —CH₃/H ,5-di-OCHF₂

henyl  .10/7.61 21

The present invention also provides pharmaceutical compositionscontaining compounds of formula I or pharmaceutically usable acidaddition salts thereof and a pharmaceutically acceptable carrier. Suchpharmaceutical compositions can be in the form of tablets, coatedtablets, dragées, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The pharmaceutical compositions also can be in the formof suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of formula I or a pharmaceutically usable acid additionsalt thereof, contain a pharmaceutically acceptable excipient. Suitablepharmaceutically inert excipients include pharmaceutically inert,inorganic or organic excipients for the production of tablets, coatedtablets, dragées and hard gelatine capsules. Lactose, corn starch orderivatives thereof, talc, stearic acid or its salts etc. can be used assuch excipients e.g. for tablets, dragées and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils,waxes, fats, semi-solid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g.water, polyols, saccharose, invert sugar, glucose etc.

Suitable excipients for injection solutions are e.g. water, alcohols,polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositories are e.g. natural or hardened oils,waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical compositions of the invention can containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, masking agents or antioxidants. They can also containstill other therapeutically valuable substances.

Compounds of the present invention are dual NK-1/NK-3 antagonists.Therefore, the present invention also provides a method for thetreatment of schizophrenia. Such method includes administering atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable addition salt thereof, to an individual. Inparticular, such method includes administering a therapeuticallyeffective amount of a compound of formula I-1, or a pharmaceuticallyacceptable acid addition salt thereof, to an individual.

In individual embodiments, the present invention provides methods forthe treatment of schizophrenia which comprise administering to anindividual an effective amount of a compound of formula IA, IB, IC, ID,IE, IF, IG, IH, IJ, or a pharmaceutically acceptable acid addition saltof any one or more of these compounds.

The compounds and compositions of the invention can be administered in aconventional manner, for example, orally, rectally, or parenterally. Thepharmaceutical compositions of the invention can be administered orally,for example, in the form of tablets, coated tablets, dragées, hard andsoft gelatine capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be administered rectally, forexample, in the form of suppositories or parenterally, for example, inthe form of injectable solutions.

The dosage at which the compound of the invention is administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula I should be appropriate, although the aboveupper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

Intermediate 1 (6-Chloro-4-iodo-pyridin-3-yl)-methyl-carbamic Acidtert-butyl Ester

To a solution of 1.00 g (2.82 mmol)(6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester in 10 mlDMF were added 0.12 g (3.1 mmol) sodium hydride (60% in mineral oil) at−10° C. (The preparation of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acidtert-butyl ester has been described in US 2002/0022624 A1.) The reactionmixture was allowed to warm to room temperature. After 1 h, the mixturewas cooled back to −10° C., and 0.44 ml (7.1 mmol) iodomethane wereadded during 5 min. The reaction mixture was allowed to warm to roomtemperature. After 2.5 h at room temperature, the reaction was quenchedby addition of 10 ml of a saturated aqueous solution of NaHCO₃ and themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography (silica gel,hexanes/ethyl acetate=4:1) to give 1.06 g (100%) of the title compoundas a colorless oil.

MS m/e (%): 368 (M⁺, 1)

Intermediate 2 (6-Chloro-4-iodo-pyridin-3-yl)-methyl-amine

To a solution of 8.65 g (19.6 mmol)(6-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester in20 ml dichloromethane were added 20.0 ml (261 mmol) trifluoroacetic acidat 0° C. After stirring for 2 h at room temperature the reaction mixturewas concentrated in vacuo. The residue was treated with 50 ml saturatedsodium carbonate solution and extracted three times with 75 ml ethylacetate. The combined organic layers were washed with 50 ml brine, driedover sodium sulfate and concentrated in vacuo to give 6.1 g (87%) of thetitle compound as a light brown solid.

MS m/e (%): 268 (M⁺, 1)

Intermediate 3A [6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine

A mixture of 6.05 g (19.3 mmol)(6-chloro-4-iodo-pyridin-3-yl)-methyl-amine, 23.6 g (23.6 mmol)2-chlorophenylboronic acid, 441 mg (1.96 mmol) palladium(II) acetate,1.03 g (3.93 mmol) triphenylphosphine, 47.1 ml 2 N sodium carbonatesolution and 50 ml 1,2-dimethoxyethane was heated at 80° C. for 90 min.The reaction mixture was cooled to room temperature and diluted with 100ml ethyl acetate. The aqueous layer was separated and extracted with 100ml ethyl acetate. The combined organic layers were dried over sodiumsulfate, concentrated in vacuo and purified by flash chromatography togive 4.1 g (83%) of the title compound as a light brown solid.

MS m/e (%): 253 (M+H⁺, 100)

Intermediate 3B [4-(2-Bromo-phenyl)-6-chloro-pyridin-3-yl]-methyl-amine

The title compound was obtained as a brown solid in 86% yield afterflash chromatography according to the procedure described above for thepreparation of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amineusing 2-bromophenylboronic acid instead of 2-chlorophenylboronic acid.

MS m/e (%): 297 (M+H⁺, 85)

Intermediate 3C[6-Chloro-4-(2-chloro-4-fluoro-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as a light brown solid in 69% yieldafter flash chromatography according to the procedure described abovefor the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using2-chloro-4-fluorophenylboronic acid instead of 2-chlorophenylboronicacid.

MS m/e (%): 271 (M+H⁺, 100)

Intermediate 3D[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as a orange solid in 80% yield afterflash chromatography according to the procedure described above for thepreparation of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amineusing 4-fluoro-2-methyl-phenylboronic acid instead of2-chlorophenylboronic acid.

MS m/e (%): 251 (M+H⁺, 100)

Intermediate 3E[6-Chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as an off-white solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using3-fluoro-2-methyl-phenylboronic acid instead of 2-chlorophenylboronicacid.

MS m/e (%): 251 (M+H⁺, 100)

Intermediate 3F[6-Chloro-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as an off-white solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using5-fluoro-2-methyl-phenylboronic acid instead of 2-chlorophenylboronicacid.

MS m/e (%): 251 (M+H⁺, 100)

Intermediate 3G (6-Chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine

The title compound was obtained as a light brown solid in 92% yieldafter flash chromatography according to the procedure described abovefor the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine usingo-tolylboronic acid instead of 2-chlorophenylboronic acid.

MS m/e (%): 233 (M+H⁺, 100)

Intermediate 3H[6-Chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as a light brown solid in 70% yieldafter flash chromatography according to the procedure described abovefor the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using2,4-dichlorophenylboronic acid instead of 2-chlorophenylboronic acid.

MS m/e (%): 287 (M+H⁺, 100)

Intermediate 3I[6-Chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as a light brown solid in 68% yieldafter flash chromatography according to the procedure described abovefor the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using3,4-dichlorophenylboronic acid instead of 2-chlorophenylboronic acid.

MS m/e (%): 287 (M+H⁺, 100)

Intermediate 3J [6-Chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as an off-white solid in comparableyield according to the procedure described above for the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using4-fluorophenylboronic acid instead of 2-chlorophenylboronic acid.

MS m/e (%): 237 (M+H⁺, 100)

Intermediate 3K[6-Chloro-4-(3-chloro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine a)3-Chloro-2-methyl-phenylboronic Acid

To a solution of 10.0 g (48.7 mmol) 2-bromo-6-chlorotoluene and 11.3 ml(48.7 mmol) triisopropyl borate in 90 ml dry THF were added dropwise 30ml (49 mmol) of a 1.6 M solution on n-butyllithium in hexanes at −78° C.under argon. After 45 min the reaction mixture was allowed to warm toroom temperature. The reaction was quenched by addition of 5 ml waterand the solvent was evaporated in vacuo. Addition of 1 M aqueoushydrochloric acid solution was followed by extraction with four portionsof dichloromethane. The combined organic extracts were dried over sodiumsulfate and concentrated in vacuo. Crystallisation from heptane gave5.08 g (61%) of the title compound as a white solid.

b) [6-Chloro-4-(3-chloro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine

The title compound was obtained as an off-white solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (Intermediate3A) using 3-chloro-2-methyl-phenylboronic acid instead of2-chlorophenylboronic acid.

Intermediate 3L{4-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl}-methyl-aminea) [2-(2-Chloro-5-methylamino-pyridin-4-yl)-phenyl]-methanol

The title compound was obtained as a yellow oil in comparable yieldaccording to the procedure described above for the preparation of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine using2-(hydroxymethyl)benzeneboronic acid instead of 2-chlorophenylboronicacid.

MS m/e (%): 249 (M+H⁺, 100)

b){4-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl}-methyl-amine

The crude title compound was obtained as a yellow oil in quantitativeyield after extraction according to the procedure described above forthe preparation of(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine(Example 174a)) using[2-(2-chloro-5-methylamino-pyridin-4-yl)-phenyl]-methanol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol.

MS m/e (%): 363 (M+H⁺, 100)

Intermediate 4A2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 20 g (79 mmol)[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine in 200 mltetrahydrofuran were added dropwise at 0° C. 113 ml (94.8 mmol) of a0.91 M solution of potassium bis(trimethylsilyl)amide intetrahydrofuran. The reaction mixture was stirred at room temperaturefor 30 min. After cooling to 0° C. 27.7 g (86.9 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride wereadded dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred at room temperature for 1 h. The reactionmixture was treated with 220 ml 1 N sodium hydrogencarbonate solutionand extracted with three 200-ml portions of ethyl acetate. The combinedorganic layers were dried over sodium sulfate and triturated with 150 mldiethylether to give 34.6 g (82%) of the title compound as a whitesolid.

MS m/e (%): 535 (M+H⁺, 100)

Intermediate 4B2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 68% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-methyl-amine instead of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 579 (M+H⁺, 98)

Intermediate 4C2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 52% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(2-chloro-4-fluoro-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 553 (M+H⁺, 100)

Intermediate 4D2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 87% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 533 (M+H⁺, 100)

Intermediate 4E2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 78% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 533 (M+H⁺, 100)

Intermediate 4F2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 533 (M+H⁺, 100)

Intermediate 4G2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 78% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine instead of[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 514 (M⁺, 5)

Intermediate 4H2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 57% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 569 (M+H⁺, 100)

Intermediate 4I2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 45% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 569 (M+H⁺, 100)

Intermediate 4J2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 92% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing [6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 519 (M+H⁺, 100)

Intermediate 4K2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-chloro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 49% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4A) using[6-chloro-4-(3-chloro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 549 (M+H⁺, 100)

Intermediate 4L2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light yellow oil in 76% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideusing{4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl}-methyl-amineinstead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.

MS m/e (%): 645 (M+H⁺, 100)

Intermediate 5A 2-(3,5-Dichloro-phenyl)-2-methyl-propionyl Chloride a)2-(3,5-Dichloro-phenyl)-2-methyl-propionic Acid Methyl Ester

A solution of 18.2 g (82.8 mmol) (3,5-dichloro-phenyl)-acetic acidmethyl ester in 15 ml THF was added to a solution of lithiumdiisopropylamide in THF (obtained by adding 49.7 ml (99.4 mmol) of a 2 Msolution of lithium diispropylamide in THF/heptane/ethylbenzene to 125ml THF at −20° C. After stirring for 45 min. 6.3 ml (99.4 mmol) methyliodide in 12 ml THF was added at the same temperature over a period of30 min. To this solution another 49.7 ml (99.4 mmol) lithiumdiisopropylamide solution (2 M) in THF/heptane/ethylbenzene was added at−20° C. followed by 6.3 ml (99.4 mmol) methyl iodide in 12 ml THF. Afterstirring for 2 h at ambient temperature the solution was poured into 500ml 2 N hydrochloric acid solution and extracted three times with 300 mlCH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash-chromatography (SiO₂,CH₂Cl₂/hexanes 1:2) to yield 17.0 g (83%)2-(3,5-dichloro-phenyl)-2-methyl-propionic acid methyl ester as a lightyellow oil.

MS m/e (%): 246 (M⁺, 38), 187 (100).

b) 2-(3,5-Dichloro-phenyl)-2-methyl-propionic Acid

To a solution of 9.0 g (36 mmol)2-(3,5-dichloro-phenyl)-2-methyl-propionic acid methyl ester in 40 mlethanol 40 ml 2 N sodium hydroxide solution was added. After stirringfor 4 hrs at RT 150 ml water was added and the solution washed twicewith 200 ml Et₂O. The aqueous phase was acidified with 25% hydrochloricacid solution and three times extracted with 150 ml CH₂Cl₂. The combinedorganic layers were dried (Na₂SO₄), filtered and evaporated to yield 8.3g (97%) 2-(3,5-dichloro-phenyl)-2-methyl-propionic acid as a off-whitesolid.

MS m/e (%): 232 (M⁺, 28), 187 (100).

c) 2-(3,5-Dichloro-phenyl)-2-methyl-propionyl Chloride

To a solution of 8.3 g (35.6 mmol)2-(3,5-dichloro-phenyl)-2-methyl-propionic acid in 80 ml CH₂Cl₂ and 4drops DMF 6.1 ml (71.2 mmol) oxalyl chloride was added at 0° C. and theresulting mixture stirred for 12 h After evaporation of the solvent 8.3g (93%) 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride was obtainedas a light yellow oil, which was used without further purification.

Intermediate 5B 2-(3-Fluoro-5-trifluoromethyl-phenyl)-2-methyl-propionylChloride

The title compound was obtained as a yellow oil in an analogous mannerto that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3-fluoro-5-trifluoromethyl-phenyl)-acetic acid methylester in step a).

Intermediate 5C 2-Methyl-2-(3-trifluoromethyl-phenyl)-propionyl Chloride

The title compound was obtained as a yellow oil in an analogous mannerto that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3-trifluoromethyl-phenyl)-acetic acid methyl ester instep a).

Intermediate 5D 2-(3,5-Difluoro-phenyl)-2-methyl-propionyl Chloride

The title compound was obtained as a yellow oil in analogous manner tothat described for 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chlorideusing (3,5-difluoro-phenyl)-acetic acid methyl ester in step a).

Intermediate 5E 2-(3-Chloro-5-methoxy-phenyl)-2-methyl-propionylChloride

The title compound was obtained as a yellow oil in an analogous mannerto that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3-chloro-5-methoxy-phenyl)-acetic acid methyl ester instep a).

Intermediate 5F 2-(3,5-Dimethyl-phenyl)-2-methyl-propionyl Chloride

The title compound was obtained as a yellow oil in an analogous mannerto that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3,5-dimethyl-phenyl)-acetic acid methyl ester in stepa).

Intermediate 5G 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionylChloride

The title compound is obtained according to the procedure described inWO 0279134 A1.

Intermediate 5H 2-(3,5-Dimethoxy-phenyl)-2-methyl-propionyl Chloride

The title compound was obtained as a light red oil in an analogousmanner to that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3,5-dimethoxy-phenyl)-acetic acid ethyl ester in stepa).

Intermediate 5I 2-Methyl-2-(3-trifluoromethoxy-phenyl)-propionylChloride

The title compound was obtained as a light yellow oil in an analogousmanner to that described for 2-(3,5-dichloro-phenyl)-2-methyl-propionylchloride using (3-trifluoromethoxy-phenyl)-acetic acid ethyl ester instep a).

Example 1N-[4-(2-Chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

To a solution of 1.20 g (4.74 mmol)[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 1.43 g(5.68 mmol) 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride in 20 mltoluene 1.27 g (10.42 mmol) 4-dimethylaminopyridine was added and theresulting solution stirred at 120° for 48 h. After cooling to ambienttemperature, the solution was poured into 100 ml 0.5 N NaHCO₃-solutionand extracted three times with 50 ml CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash-chromatography (SiO₂, hexanes/ethyl acetate 4:1) to give 1.90 g(85%) of the title compound as a white solid.

MS m/e (%): 469.1 (M+H⁺, 100).

b)N-[4-(2-Chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

A solution of 0.14 g (0.29 mmol)N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand 4 ml ethanolamine was stirred at 130° for 9 h. After cooling toambient temperature, the solution was poured into 20 ml 0.5NNaHCO₃-solution and extracted three times with 30 ml CH₂Cl₂. Thecombined organic layers were dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash-chromatography (SiO₂, CH₂Cl₂/ethylacetate 1:3) to give 0.08 g (54%) of the title compound as a white foam.

MS m/e (%): 492.2 (M+H⁺, 100).

Example 2(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

To a solution of 0.15 g (0.32 mmol)N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand 0.25 g (2.47 mmol) L-prolinol in 2 ml dimethyl sulfoxide 0.2 g (1.55mmol) Na₂CO₃ was added and the solution was stirred at 13° C. for 22 h.After cooling to ambient temperature, the solution was poured into 20 ml0.5 N NaHCO₃-solution and extracted three times with 30 ml CH₂Cl₂. Thecombined organic layers were dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash-chromatography (SiO₂, CH₂Cl₂/ethylacetate 1:2) to give 0.15 g (87%) of the title compound as a white foam.

MS m/e (%): 532.2 (M+H⁺, 100).

Example 3(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

To a solution of 0.15 g (0.32 mmol)N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand 0.25 g (2.13 mmol) (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine in2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na₂CO₃ was added and thesolution was stirred at 13° C. for 9 h After cooling to ambienttemperature, the solution was poured into 20 ml 0.5 N NaHCO₃-solutionand extracted three times with 30 ml CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash-chromatography (SiO₂, CH₂Cl₂/ethyl acetate 1:2) to give 0.05 g(31%) of the title compound as a white foam. MS m/e (%): 548.3 (M+H⁺,100).

Example 4(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and2-(3-fluoro-5-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as awhite solid.

MS m/e (%): 485.3 (M+H⁺, 100).

b)(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 550.3 (M+H⁺, 100).

Example 5(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 566.3 (M+H⁺, 100).

Example 6(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-difluoro-phenyl)-2-methyl-propionyl chloride as a light yellowsolid.

MS m/e (%): 435.2 (M+H⁺, 100).

b)(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam. MS m/e (%): 516.3 (M+H⁺, 100).

Example 7(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and2-(3-chloro-5-methoxy-phenyl)-2-methyl-propionyl chloride as a lightyellow solid.

MS m/e (%): 463.2 (M+H⁺, 100).

b)(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 528.2 (M+H⁺, 100).

Example 8(2S,4R)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam. MS m/e (%): 544.3 (M+H⁺, 100).

Example 9(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-dimethyl-phenyl)-2-methyl-propionyl chloride as a white solid.

MS m/e (%): 427.1 (M+H⁺, 100).

b)(S)-N-[4-(2-Chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 492.3 (M+H⁺, 100).

Example 10(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam. MS m/e (%): 508.3 (M+H⁺, 100).

Example 11(S)-2-(3,5-Dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride as a white solid. MSm/e (%): 449.2 (M+H⁺, 100).

b)(S)-2-(3,5-Dichloro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 512.4 (M+H⁺, 100).

Example 12(2S,4R)-2-(3,5-Dichloro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 528.3 (M+H⁺, 100).

Example 13(S)-2-(3-Fluoro-5-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin Example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3-fluoro-5-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as awhite foam.

MS m/e (%): 465.2 (M+H⁺, 100).

b)(S)-2-(3-Fluoro-5-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 530.2 (M+H⁺, 100).

Example 14(2R,4S)-2-(3-Fluoro-5-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a orange foam.

MS m/e (%): 546.3 (M+H⁺, 100).

Example 15(S)-2-(3,5-Difluoro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3,5-difluoro-phenyl)-2-methyl-propionyl chloride as a light yellowsolid.

MS m/e (%): 415.2 (M+H⁺, 100).

b)(S)-2-(3,5-Difluoro-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramideand L-prolinol as a light yellow foam.

MS m/e (%): 480.2 (M+H⁺, 100).

Example 16(2S,4R)-2-(3,5-Difluoro-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a orange foam.

MS m/e (%): 496.4 (M+H⁺, 100).

Example 17(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3-Chloro-5-methoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3-chloro-5-methoxy-phenyl)-2-methyl-propionyl chloride as a lightyellow solid.

MS m/e (%): 443.1 (M+H⁺, 100).

b)(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3-chloro-5-methoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 508.2 (M+H⁺, 100).

Example 18(2S,4R)-2-(3-Chloro-5-methoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3-chloro-5-methoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 524.3 (M+H⁺, 100).

Example 19(S)-2-(3,5-Dimethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained to that described in example 1a) from(6-Chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3,5-dimethyl-phenyl)-2-methyl-propionyl chloride as a light yellowfoam.

MS m/e (%): 407.1 (M+H⁺, 100).

b)(S)-2-(3,5-Dimethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-O-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 472.3 (M+H⁺, 100).

Example 20(2S,4R)-2-(3,5-Dimethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 488.3 (M+H⁺, 100)

Example 212-(3,5-Dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide

The title compound was obtained to that described in example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride as a white foam.

MS m/e (%): 464.1 (M⁺, 5).

b)2-(3,5-Dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1b) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand ethanolamine as a white foam.

MS m/e (%): 490.2 (M+H⁺, 100).

Example 22(S)-2-(3,5-Dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 530.2 (M+H⁺, 100).

Example 23(2S,4R)-2-(3,5-Dichloro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam. MSm/e (%): 546.2 (M+H⁺, 100).

Example 24(S)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3-fluoro-5-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as awhite foam.

MS m/e (%): 483.2 (M+H⁺, 100).

b)(S)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 548.4 (M+H⁺, 100).

Example 25(2S,4R)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-fluoro-5-trifluoromethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 564.4 (M+H⁺, 100).

Example 26(S)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-methyl-2-(3-trifluoromethyl-phenyl)-propionyl chloride as a whitesolid.

MS m/e (%): 465.4 (M+H⁺, 100).

b)(S)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 530.3 (M+H⁺, 100).

Example 27(2S,4R)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethyl-phenyl)-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 546.3 (M+H⁺, 100).

Example 28(S)-2-(3,5-Difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-difluoro-phenyl)-2-methyl-propionyl chloride as a white solid.

MS m/e (%): 433.3 (M+H⁺, 100).

b)(S)-2-(3,5-Difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramideand L-prolinol as a light yellow foam.

MS m/e (%): 498.3 (M+H⁺, 100).

Example 29(2S,4R)-2-(3,5-Difluoro-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 513.2 (M⁺), 482.2 (100).

Example 30(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3-chloro-5-methoxy-phenyl)-2-methyl-propionyl chloride as a waxysolid.

MS m/e (%): 461.1 (M+H⁺, 100).

b)(S)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 526.2 (M+H⁺, 100).

Example 31(2S,4R)-2-(3-Chloro-5-methoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 542.2 (M+H⁺, 100).

Example 32(S)-(3,5-Dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-dimethyl-phenyl)-2-methyl-propionyl chloride as a white foam.

MS m/e (%): 425.2 (M+H⁺, 100).

b)(S)-(3,5-Dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 490.4 (M+H⁺, 100).

Example 33(2S,4R)-2-(3,5-Dimethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethyl-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 506.3 (M+H⁺, 100).

Example 34(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-hydroxy-phenyl)-N-methyl-isobutyramide

To a solution of 1.10 g (2.37 mmol)N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramidein 20 ml CH₂Cl₂ 4.74 ml (4.74 mmol) BBr₃ (1 M in CH₂Cl₂) was added at 0°C. The reaction mixture was allowed to reach ambient temperature andstirred for 6 h After addition of 50 ml water the mixture was extractedthree times with 60 ml CH₂Cl₂. The combined organic solvents were dried(Na₂SO₄), filtered and evaporated. The residue was purified byflash-chromatography (SiO₂, CH₂Cl₂/ethyl acetate 4:1) to give 0.70 g(65%) of the title compound as a white foam. MS m/e (%): 449.1 (M+H⁺,100).

b)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-difluoromethoxy-phenyl)-N-methyl-isobutyramide

To a solution of 0.700 g (1.56 mmol)N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-hydroxy-phenyl)-N-methyl-isobutyramidein 10 ml N,N-Dimethylformamide 0.215 g (1.56 mmol) K₂CO₃ and 0.2 ml(1.56 mmol) ethyl chlordifluoroacetate was added and the resultingsuspension heated at 65° C. for 15 h. After cooling to ambienttemperature, the reaction mixture was poured into 75 ml water andextracted three times with 80 ml CH₂Cl₂. The combined organic solventswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash-chromatography (SiO₂, CH₂Cl₂/ethyl acetate 4:1) to give 0.38 g(49%) of the title compound as a white solid.

MS m/e (%): 499.1 (M+H⁺, 100).

c)(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2 fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-difluoromethoxy-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 564.2 (M+H⁺, 100).

Example 35(2S,4R)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-difluoromethoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 580.5 (M+H⁺, 100).

Example 36(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3-Chloro-5-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 34a), b) from2-(3-chloro-5-methoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideas a white foam.

MS m/e (%): 479.1 (M+H⁺, 100).

b)(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3-chloro-5-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 544.3 (M+H⁺, 100).

Example 37(2S,4R)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3-chloro-5-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 560.3 (M+H⁺, 100).

Example 38(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 34a), b) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3-chloro-5-methoxy-phenyl)-N-methyl-isobutyramideas a white foam.

MS m/e (%): 497.1 (M+H⁺, 100).

b)(S)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2S-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 562.2 (M+H⁺, 100).

Example 39(2S,4R)-2-(3-Chloro-5-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3-chloro-5-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light brown foam.

MS m/e (%): 578.3 (M+H⁺, 100).

Example 40(2S,4S)-N-[6-(4-Acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 30 mg (0.056 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,200 mg (1.27 mmol) (2S,4S)-4-acetylamino-2-hydroxymethyl-pyrrolidine and0.2 ml dimethyl sulfoxide was heated at 130° C. for 24 h. After coolingto room temperature, 22 mg (59%) of the title compound were isolated asa white solid by automated, preparative HPLC (YMC CombiPrep C18 column50×20 mm, solvent gradient 5-95% CH₃CN in 0.1% TFA(aq) over 6.0 min,λ=230 nm, flow rate 40 ml/min).(2S,4S)-4-Acetylamino-2-hydroxymethyl-pyrrolidine can be obtained by themethod described by Terry Rosen, Daniel T. W. Chu, Isabella M. Lico,Isabella M. Lico, Prabhavathi B. Fernandes, Kennan Marsh, Linus Shen,Valerie G. Cepa, André G. Pernet, J. Med. Chem. 1988, 31, 1598. MS m/e(%): 657 (M+H⁺)

Example 41(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from D-prolinol as a light grey solid in8% yield according to the procedure described above for the preparationof(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 600 (M+H⁺)

Example 42(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from L-prolinol as a white solid in 49%yield according to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 600 (M+H⁺)

Example 43(S)-N-[6-(3-Acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained from (S)-3-acetamidopyrrolidine as awhite solid in 42% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 627 (M+H⁺)

Example 44(R)-N-[6-(3-Acetylamino-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained from (R)-3-acetamidopyrrolidine as awhite solid in 56% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 627 (M+H⁺)

Example 45(RS)-N-[6-[3-(Acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained from(RS)-3-(N-acetyl-N-ethylamino)pyrrolidine as a white solid in 54% yieldaccording to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 655 (M+H⁺)

Example 46(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from (S)-3-pyrrolidinol as a light greysolid in 7% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 586 (M+H⁺)

Example 47(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from (R)-3-pyrrolidinol as an off-whitesolid in 30% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 586 (M+H⁺)

Example 48(3R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from (3R,4S)-pyrrolidin-3,4-diol as awhite solid in 47% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.(3R,4S)-Pyrrolidine-3,4-diol can be obtained by the method described byAlbert Defoin, Joaquim Pires, Jaques Streith, Helv. Chim. Acta 1991, 74,1653.

MS m/e (%): 602 (M+H⁺)

Example 49(3R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from (3R,4R)-pyrrolidin-3,4-diol as awhite solid in 61% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 602 (M+H⁺)

Example 50(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained from (RS)-3-piperidinol as a white solidin 55% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 600 (M+H⁺)

Example 512-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained from 4-hydroxypiperidine as a whitesolid in 47% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 600 (M+H⁺)

Example 522-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained from 4-(hydroxymethyl)-piperidine as awhite foam in 43% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 614 (M+H⁺)

Example 53(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained from (RS)-2-piperidin-2-yl-ethanol as alight yellow solid in 5% yield according to the procedure describedabove for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 628 (M+H⁺)

Example 542-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained from N-methylethanolamine as a whitesolid in 54% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 574 (M+H⁺)

Example 552-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[ethyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained from 2-ethylamino-ethanol as a whitesolid in 50% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 588 (M+H⁺)

Example 562-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-propyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained from N-propylethanolamine as a whitesolid in 34% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 602 (M+H⁺)

Example 572-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[butyl-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from N-butylethanolamine as a colorlesswaxy solid in 37% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 616 (M+H⁺)

Example 58(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[(2,3-dihydroxy-propyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained from(RS)-2,3-dihydroxy-N-methylpropylamine as a white solid in 48% yieldaccording to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 604 (M+H⁺)

Example 59(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(1-hydroxymethyl-3-methyl-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from L-leucinol as a white solid in 42%yield according to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 616 (M+H⁺)

Example 60trans-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from trans-4-aminocyclohexanol as awhite solid in 42% yield according to the procedure described above forthe preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 614 (M+H⁺)

Example 61N-[6-(4-Acetyl-piperazin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained from 1-acetylpiperazine as a white solidin 52% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 627 (M+H⁺)

Example 622-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-cyclopropanecarbonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from 1-cyclopropylcarbonylpiperazine asa white solid in 32% yield according to the procedure described abovefor the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 653 (M+H⁺)

Example 63N-[6-(4-Acetyl-[1,4]diazepan-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained from 1-acetylhomopiperazine as a whitesolid in 50% yield according to the procedure described above for thepreparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 641 (M+H⁺)

Example 64(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from(S)-(+)-1-(2-pyrrolidinyl-methyl)pyrrolidine as a white solid in 54%yield according to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 653 (M+H⁺)

Example 65(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-dimethylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from(S)-(−)-3-(dimethylamino)pyrrolidine as a white solid in 56% yieldaccording to the procedure described above for the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 613 (M+H⁺)

Example 66(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-methanesulfonyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained from (RS)-3-methylsulfonylpyrrolidine asa white solid in 57% yield according to the procedure described abovefor the preparation of(2S,4S)-N-[6-(4-acetylamino-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 648 (M+H⁺)

Example 672-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 28.6 g (56 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,50 ml dimethyl sulfoxide and 50 ml (830 mmol) ethanolamine was stirredat 140° C. for 24 h. The reaction mixture was cooled to roomtemperature, diluted with 200 ml ethyl acetate and washed with 200 ml 1N sodium carbonate solution and 100 ml water. The aqueous layers wereextracted with two 200-ml portions of ethyl acetate. The combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.The residue was crystallized from a mixture of 150 ml diisopropyl etherand 150 ml heptane to give 29.1 g (93%) of the title compound as whitecrystals. M.p. 117-118° C.

MS m/e (%): 560 (M+H⁺, 100)

Example 682-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 28% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 558 (M+H⁺, 100)

Example 692-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 48% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 578 (M+H⁺, 100)

Example 702-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 91% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 594 (M+H⁺, 100)

Example 71(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 78% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (S)-1-amino-2-propanol instead of ethanolamine.

MS m/e (%): 608 (M+H⁺, 100)

Example 72(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 65% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-1-amino-2-propanol instead of ethanolamine. MS m/e (%): 574(M+H⁺, 100)

Example 73(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 84% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (R)-1-amino-2-propanol instead of ethanolamine. MS m/e (%): 574(M+H⁺, 100)

Example 74(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 79% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (RS)-1-amino-2-propanol instead of ethanolamine.

MS m/e (%): 574 (M+H⁺, 100)

Example 752-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-2-methyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 457 mg (3.60 mmol) oxalyl chloride in 17 mldichloromethane was added dropwise during 5 minutes at −75° C. asolution of 562 mg (7.20 mmol) dimethyl sulfoxide in 5 mldichloromethane. After stirring for 5 minutes a solution of 1.72 g (3.00mmol)(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramidein 5 ml dichloromethane was added dropwise at −65° C. Stirring wascontinued at −70° C. for 1 h, followed by addition of 2.6 ml (15 mmol)ethyldiisopropylamine. After stirring at room temperature for 3 h thereaction mixture was diluted with 20 ml dichloromethane and washed with20 ml water, 20 ml 1 N hydrochloric acid solution and 20 ml saturatedsodium carbonate solution. The combined organic layers were dried oversodium sulfate, concentrated in vacuo and purified by flashchromatography to give 1.45 g (85%) of the title compound as a whitefoam.

MS m/e (%): 572 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-2-methyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 100 mg (0.175 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramidein 1 ml tetrahydrofuran was added a 3 N solution of methylmagnesiumbromide in diethyl ether at room temperature. The reaction mixture wasstirred at room temperature for 1 h and at 65° C. for 3 h. After coolingto room temperature few drops of a 1 N aqueous solution of hydrochloricacid were added to the reaction mixture, followed by extraction withdichloromethane and washing with saturated sodium carbonate solution.The combined organic layers were dried over sodium sulfate, concentratedin vacuo and purified by flash chromatography to give 51 mg (50%) of thetitle compound as a white foam.

MS m/e (%): 588 (M+H⁺, 100)

Example 762-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-butylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 55% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing 1-amino-2-butanol instead of ethanolamine.

MS m/e (%): 588 (M+H⁺, 100)

Example 77(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 59% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-1-amino-2-propanol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 572 (M+H⁺, 100)

Example 78(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 100% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (RS)-3-amino-1,2-propandiol instead of ethanolamine.

MS m/e (%): 590 (M+H⁺, 100)

Example 79(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 14% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing L-alaninol instead of ethanolamine.

MS m/e (%): 574 (M+H⁺, 100)

Example 80(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 24% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (R)-2-amino-1-propanol instead of ethanolamine.

MS m/e (%): 574 (M+H⁺, 100)

Example 812-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 34% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-amino-1,3-propandiol instead of ethanolamine.

MS m/e (%): 590 (M+H⁺, 100)

Example 82N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 41% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine.

MS m/e (%): 604 (M+H⁺, 100)

Example 83N-{6-[Bis-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 55% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 584 (M+H⁺, 100)

Example 84N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 52% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 602 (M+H⁺, 100)

Example 852-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 15% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing 3-(2-hydroxyethylamino)-1-propanol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 616 (M+H⁺, 100)

Example 86N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 48% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.and diethanolamine instead of ethanolamine.

MS m/e (%): 638 (M+H⁺, 100)

Example 87N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 65% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand diethanolamine instead of ethanolamine.

MS m/e (%): 638 (M+H⁺, 100)

Example 88N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 68% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 588 (M+H⁺, 100)

Example 892-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 30% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(methylthio)ethylamine instead of ethanolamine.

MS m/e (%): 590 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 50 mg (0.087 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideand 130 mg (0.212 mmol) potassium monopersulfate triple salt in 1 mlmethanol was stirred at room temperature for 3 days. The reaction wasquenched with 1 ml sodium hydrogen sulfite solution 38%. The mixture wastreated with 3 ml saturated sodium carbonate solution and extracted withthree 5-ml portions of ethyl acetate. The combined organic layers weredried over sodium sulfate, concentrated in vacuo and purified by flashchromatography to give 29 mg (55%) of the title compound as a whitefoam.

MS m/e (%): 622 (M+H⁺, 100)

Example 90N-[6-(2-Acetylamino-ethylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 65% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing N-acetylethylenediamine instead of ethanolamine.

MS m/e (%): 601 (M+H⁺, 100)

Example 91trans-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 42% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand trans-4-aminocyclohexanol instead of ethanolamine.

MS m/e (%): 648 (M+H⁺, 100)

Example 92trans-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 23% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing trans-4-aminocyclohexanol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 612 (M+H⁺, 100)

Example 93(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 58% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing D-prolinol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 598 (M+H⁺, 100)

Example 94(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 96% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.and D-prolinol instead of ethanolamine.

MS m/e (%): 634 (M+H⁺, 100)

Example 95(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 97% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand D-prolinol instead of ethanolamine.

MS m/e (%): 634 (M+H⁺, 100)

Example 96(2R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 76% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (2R,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead ofethanolamine.

MS m/e (%): 616 (M+H⁺, 100)

Example 97(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 62% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead ofethanolamine.

MS m/e (%): 616 (M+H⁺, 100)

Example 982-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 23% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing azetidin-3-ol instead of ethanolamine.

MS m/e (%): 572 (M+H⁺, 100)

Example 99(S)-N-[6-(3-Acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 58% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-3-acetamidopyrrolidine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 625 (M+H⁺, 100)

Example 100(R)-N-[6-(3-Acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 75% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (R)-3-acetamidopyrrolidine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 625 (M+H⁺, 100)

Example 101(R)-N-[6-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 146 mg (0.234 mmol)(R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 5 ml tetrahydrofuran were added dropwise at room temperature 0.31 ml(0.28 mmol) of a 0.91 N potassium bis(trimethylsilyl)amide solution intetrahydrofuran. After stirring at room temperature for 30 min. 43 mg(30 mmol) iodomethane were added. The reaction mixture was stirred atroom temperature for 18 h, followed by dilution with 10 ml ethyl acetateand washing with 10 ml saturated sodium carbonate solution. The combinedorganic layers were dried over sodium sulfate, concentrated in vacuo andpurified by flash chromatography to give 130 mg (87%) of the titlecompound as a white foam.

MS m/e (%): 639 (M+H⁺, 100)

Example 102(R)-N-[6-[3-(Acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 41% yield after flashchromatography according to the procedure described above for thepreparation of(R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing iodoethane instead of iodomethane.

MS m/e (%): 653 (M+H⁺, 100)

Example 103(S)-N-[6-(3-Amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 975 mg (1.83 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,1.26 g (9.15 mmol) potassium carbonate and 800 mg (3.66 mmol)(S)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 10 ml dimethylsulfoxide was stirred at 130° C. for 52 h. After cooling to roomtemperature the reaction mixture was diluted with 30 ml tert-butylmethyl ether and washed with 20 ml of water and 10 ml of a saturatedaqueous solution of sodium carbonate. The combined organic layers weredried over sodium sulfate and concentrated. The residue was dissolved in25 ml of a 2 N solution of ammonia in ethanol. The solution was stirredat room temperature for 18 h. The reaction mixture was concentrated andpurified by flash chromatography to give 640 mg (60%) of the titlecompound as a light brown foam.

MS m/e (%): 583 (M+H⁺, 100)

Example 104(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 600 mg (1.03 mmol)(S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 6 ml dichloromethane were added 6 mg (0.05 mmol)4-(N,N-dimethylamino)pyridine, 266 mg (2.06 mmol)N,N-diisopropylethylamine and 153 mg (1.34 mmol) methanesulfonylchloride. After stirring at room temperature for 18 h the reactionmixture was diluted with 20 ml dichloromethane and washed with 20 ml ofa saturated aqueous solution of sodium carbonate. The combined organiclayers were dried over sodium sulfate, concentrated and purified byflash chromatography to give 553 mg (81%) of the title compound as anoff-white foam.

MS m/e (%): 659 ([M−H⁺]⁻, 100)

Example 105(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 48% yield afterflash chromatography according to the procedure described above for thepreparation of(R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 675 (M+H⁺, 100)

Example 106(S)-(2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 150 mg (0.227 mmol)(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein 1 ml dimethylformamide were added 14 mg (0.35 mmol) sodium hydride(60% dispersion in mineral oil). After stirring at room temperature for30 min. 22 mg (0.27 mmol) iodoethane were added. The reaction mixturewas stirred at room temperature for 18 h, followed by dilution with 10ml tert-butyl methyl ether and washing with 20 ml water and with 10 mlof a saturated aqueous solution of sodium carbonate. The combinedorganic layers were dried over sodium sulfate, concentrated and purifiedby flash chromatography to give 86 mg (55%) of the title compound as anoff-white foam.

MS m/e (%): 689 (M+H⁺, 100)

Example 107(S)-N-[6-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 62% yield after flashchromatography according to the procedure described above for thepreparation of(R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing(S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 639 (M+H⁺, 100)

Example 108(S)-N-[6-[3-(Acetyl-ethyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 59% yield after flashchromatography according to the procedure described above for thepreparation of(R)-N-[6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing(S)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(R)-N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideand iodoethane instead of iodomethane.

MS m/e (%): 639 (M+H⁺, 100)

Example 109(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 62% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-3-hydroxypyrrolidine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 584 (M+H⁺, 100)

Example 110(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 73% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (RS)-3-pyrrolidinol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 584 (M+H⁺, 100)

Example 1112-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a off-white foam in 73% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 582 (M+H⁺, 100)

Example 112N-[4-Amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 72% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 598 (M+H⁺, 100)

b)N-[4-Amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 752 mg (1.26 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein 7 ml methanol 970 mg (12.6 mmol) ammonium acetate were added at roomtemperature. The mixture was stirred 5 minutes at this temperature,cooled to 0° C. and treated with 119 mg (1.89 mmol) sodiumcyanoborohydride. The reaction mixture was allowed to slowly warm toroom temperature during 5 h, followed by dilution with 20 ml ethylacetate, washing with 10 ml brine and extraction with 20 ml ethylacetate. The combined organic layers were dried over sodium sulfate,concentrated in vacuo and purified by flash chromatography to give 480mg (64%) of the title compound as a white foam.

MS m/e (%): 600 (M+H⁺, 100)

Example 1132-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 16% yield after flashchromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusingN-[4-amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(S)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 677 (M+H⁺, 100)

Example 114N-[4-Acetylamino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 93% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 4-hydroxy-piperidine instead of ethanolamine.

MS m/e (%): 598 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 96% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

MS m/e (%): 596 (M+H⁺, 100)

c)N-[4-Amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 45% yield after flashchromatography according to the procedure described above for thepreparation ofN-[4-amino-4′-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 597 (M+H⁺, 100)

d)N-[4-Acetylamino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 80 mg (0.13 mmol)N-[4-amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideand 26 mg (0.20 mmol) N,N-diisopropylethylamine in 3 ml dichloromethanewere added 12 mg (0.15 mmol) acetyl chloride at 0° C. The reactionmixture was stirred at room temperature for 18 h. The mixture wasdiluted with 10 ml dichloromethane and washed with 10 ml of a saturatedaqueous solution of sodium carbonate. The combined organic layers weredried over sodium sulfate, concentrated and purified by flashchromatography to give 82 mg (95%) of the title compound as a whitefoam.

MS m/e (%): 639 (M+H⁺, 100)

Example 1152-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide

A mixture of 0.10 g (0.20 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 0.45 g (6.0 mmol) 2-(methylamino)ethanol was stirred 6 h at 140° C.After cooling to room temperature the reaction mixture was partitionedbetween water and tert-butyl methyl ether and extracted with threeportions of tert-butyl methyl ether. The combined organic extracts werewashed with a saturated aqueous solution of ammonium chloride and water,dried over sodium sulfate and concentrated in vacuo. Flash columnchromatography gave 87 mg (78%) of the title compound as a light yellowsolid.

MS m/e (%): 558 (M+H⁺, 100)

Example 1162-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[ethyl-(2-hydroxy-ethyl)-amino]-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 23% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol.

MS m/e (%): 572 (M+H⁺, 100)

Example 1172-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a white solid in 87% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 554 (M+H⁺, 100)

Example 1182-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[ethyl-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a white solid in 91% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol.

MS m/e (%): 568 (M+H⁺, 100)

Example 1192-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-propyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a white solid in 72% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 2-(propylamino)ethanol instead of 2-(methylamino)ethanol.

MS m/e (%): 568 (M+H⁺, 100)

Example 120(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 55% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (S)-1-amino-2-propanol instead of 2-(methylamino)ethanol.

MS m/e (%): 554 (M+H⁺, 100)

Example 121N-{6-[Bis-(2-hydroxy-propyl)-amino]-4-o-tolyl-pyridin-3-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 51% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand bis-(2-hydroxypropyl)amine instead of 2-(methylamino)ethanol.

MS m/e (%): 612 (M+H⁺, 100)

Example 122(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 76% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (S)-3-amino-1,2-propandiol instead of 2-(methylamino)ethanol.

MS m/e (%): 570 (M+H⁺, 100)

Example 123(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2,3-dihydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 74% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (R)-3-amino-1,2-propandiol instead of 2-(methylamino)ethanol.

MS m/e (%): 570 (M+H⁺, 100)

Example 124N-[6-[Bis-(2-hydroxy-propyl)-amino]-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 71% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand bis-(2-hydroxypropyl)amine instead of 2-(methylamino)ethanol.

MS m/e (%): 632 (M+H⁺, 100)

Example 125(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 73% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (S)-3-amino-1,2-propandiol instead of 2-(methylamino)ethanol.

MS m/e (%): 590 (M+H⁺, 100)

Example 126(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2,3-dihydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 65% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (R)-3-amino-1,2-propandiol instead of 2-(methylamino)ethanol.

MS m/e (%): 590 (M+H⁺, 100)

Example 127N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 34% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 2-(2-hydroxy-ethylamino)-ethanol instead of 2-(methylamino)ethanol.

MS m/e (%): 602 (M+H⁺, 100)

Example 128N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 9% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 2-(2-hydroxy-ethylamino)-ethanol instead of 2-(methylamino)ethanol.

MS m/e (%): 602 (M+H⁺, 100)

Example 129(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 800 mg (1.38 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide,4 ml dimethyl sulfoxide and 1.15 g (6.9 mmol)(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine was stirred at 130° C.for 24 h. The reaction mixture was cooled to room temperature, dilutedwith 100 ml ethyl acetate and washed with 200 ml 1 N sodium carbonatesolution and 100 ml water. The combined aqueous layers were extractedtwice with 100 ml ethyl acetate. The combined organic layers were driedover sodium sulfate and evaporated. Purification by flash chromatographygave 434 mg (48%) of the title compound as a yellow foam.

MS m/e (%): 660 (M+H⁺, 100)

Example 130(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 27% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 660 (M+H⁺, 100)

Example 131(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 52% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-1-amino-2-propanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 618 (M+H⁺, 89)

Example 132trans-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 39% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing trans-4-aminocyclohexanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 658 (M+H⁺, 83)

Example 133(S)-N-[6-(3-Acetylamino-pyrrolidin-1-yl)-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white foam in 67% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-acetamidopyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 671 (M+H⁺, 100)

Example 134N-[6-[Bis-(2-hydroxy-ethyl)-amino]-4-(2-bromo-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 23% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 648 (M+H⁺, 100)

Example 135(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 61% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 650 (M+H⁺, 100)

Example 136(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 50% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 650 (M+H⁺, 100)

Example 137(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 45% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand (2R,3S)-2-hydroxymethyl-pyrrolidin-3-ol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 650 (M+H⁺, 100)

Example 138(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 26% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand (2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 616 (M+H⁺, 100)

Example 139(2R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 67% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand (2R,4S)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 616 (M+H⁺, 100)

Example 140(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 50% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand (2S,4S)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 616 (M+H⁺, 100)

Example 141(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 45% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand (RS)-2-piperidinemethanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 614 (M+H⁺, 100)

Example 1422-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 23% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and 2-amino-1,3-propandiolinstead of (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 588 (M+H⁺, 100)

Example 1432-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-1-hydroxymethyl-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 55% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 2-amino-1,3-propandiol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 570 (M+H⁺, 100)

Example 144(1R,2R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 32% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and L-threoninol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 604 (M+H⁺, 100)

Example 145(1R,2S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 23% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and L-allo-threoninol insteadof (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 604 (M+H⁺, 100)

Example 146(1S,2R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 18% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and D-allo-threoninol insteadof (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 604 (M+H⁺, 100)

Example 147(1S,2S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-1-hydroxymethyl-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 4% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and D-threoninol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 604 (M+H⁺, 100)

Example 1482-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[hexyl-(2-hydroxy-ethyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 39% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 2-(hexylamino)ethanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 644 (M+H⁺, 100)

Example 1492-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-pentyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 38% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 2-(N-amylamino) ethanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 630 (M+H⁺, 100)

Example 1502-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 26% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 3-(hydroxyethylamino)-1-propanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 618 (M+H⁺, 100)

Example 151(1RS,2RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 46% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and(1RS,2RS)-2-aminocyclohexanol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 614 (M+H⁺, 100)

Example 152(1R,2R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)(1R,2R)-N-[6-(2-Benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a brown solid in 58% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramideand 5 mol-% 4-(N,N-dimethylamino)pyridine and(1R,2R)-2-benzyloxy-cyclopentylamine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

b)(1R,2R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.15 g (0.22 mmol)(1R,2R)-N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 2 ml dichloromethane were added 0.87 ml (0.87 mmol) of a 1 M borontrichloride solution in dichloromethane at room temperature. After 2 hthe reaction was quenched by addition of 2 ml of a 1 M aqueoushydrochloric acid solution. Neutralisation with 1 M aqueous NaOHsolution was followed by extraction with 3 portions of tert-butyl methylether. The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography gave 60 mg (46%) ofthe title compound as an off-white solid.

MS m/e (%): 600 (M+H⁺, 100)

Example 153(1S,2S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 8% yield overtwo steps according to the procedures described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing (1S,2S)-2-benzyloxy-cyclopentylamine instead of(1R,2R)-2-benzyloxy-cyclopentylamine in step a).

MS m/e (%): 600 (M+H⁺, 100)

Example 154(1S,2S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 15% yield overtwo steps according to the procedures described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (1S,2S)-2-benzyloxy-cyclopentylamine instead of(1R,2R)-2-benzyloxy-cyclopentylamine in step a).

MS m/e (%): 598 (M+H⁺, 100)

Example 155(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 11.0 g (20.6 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,14.3 g (103 mmol) potassium carbonate and 12.2 g (75.7 mmol)(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine in 110 ml dimethylsulfoxide was stirred at 130° C. for 68 h. The reaction mixture wasdiluted with 800 ml ethyl acetate and washed with 800 ml saturatedsodium carbonate solution, 500 ml water and 750 ml brine. The combinedaqueous layers were extracted with two 800-ml portions of ethyl acetate.The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Purification by flash chromatography gave 8.48 g(67%) of the title compound as a light yellow foam.

MS m/e (%): 614 (M+H⁺, 100)

Example 156(2R,3R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand Example 157(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 400 mg (0.65 mmol)(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein 6.5 ml tetrahydrofuran were added at 0° C. 0.67 ml (3.26 mmol)diisopropyl azodicarboxylate and 398 mg (3.26 mmol) benzoic acid. Thereaction mixture was cooled to −78° C., followed by addition of 855 mg(3.26 mmol) triphenylphosphine. The reaction mixture was allowed toslowly warm to room temperature over night. Addition of 75 ml of asaturated sodium carbonate solution was followed by extraction with two75-ml portions of tert-butyl methyl ether. The organic layers werewashed with 75 ml brine, dried over sodium sulfate, concentrated invacuo and purified by flash chromatography. The residue was dissolved in20 ml methanol and treated with 0.1 ml of a 5.5 M sodium methylatesolution in methanol. After stirring 3 h at room temperature thereaction mixture was concentrated in vacuo. The residue was dissolved in75 ml dichloromethane and washed with 60 ml water, dried over sodiumsulfate and purified by flash chromatography to give 117 mg (29%) of(2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideas a white foam and 155 mg (40%) of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideas a white foam.

(2R,3R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 614 (M+H⁺, 100)

(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 596 (M+H⁺, 100)

Example 158(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white foam in 66% yield afterflash chromatography according to the procedure described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 614 (M+H⁺, 100)

Example 159(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light brown amorphous material in36% yield after flash chromatography according to the proceduredescribed above for the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-2-pyrrolidin-2-yl-propan-2-ol instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 626 (M+H⁺, 100)

Example 160(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown gum in 14% yield afterflash chromatography according to the procedure described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (R)-piperidine-2-ylmethanol instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 614 (M+H⁺, 100)

Example 161(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown oil in 15% yield afterflash chromatography according to the procedure described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-piperidine-2-yl-methanol instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 614 (M+H⁺, 100)

Example 1622-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 65% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing azetidin-3-ol instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 570 (M+H⁺, 100)

Example 1632-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-azetidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 62% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing azetidin-3-ol instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 552 (M+H⁺, 100)

Example 1642-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-oxo-[1,4]diazepan-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 36% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5-(4H)-one instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 611 (M+H⁺, 100)

Example 165(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.20 g (0.38 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.23 g (2.3 mmol) L-prolinol and 0.15 g (1.1 mmol) potassium carbonatein 0.5 ml dimethyl sulfoxide was heated at 180° C. under microwaveirradiation for 30 min. in a sealed tube. After cooling to roomtemperature the reaction mixture was diluted with water and extractedwith three portions of tert-butyl methyl ether. The combined organicextracts were washed with water and brine, dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography gave 0.18 g (78%) ofthe title compound as an off-white solid.

MS m/e (%): 598 (M+H⁺, 100)

Example 166(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 47% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(5-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 598 (M+H⁺, 100)

Example 167(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 40% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 598 (M+H⁺, 100)

Example 168(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 45% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand D-prolinol instead of L-prolinol.

MS m/e (%): 580 (M+H⁺, 100)

Example 169(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 57% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine instead of L-prolinol.

MS m/e (%): 651 (M+H⁺, 100)

Example 170(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 48% yieldafter flash chromatography according to the procedure described abovefor the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 3-(methylsulfonyl)pyrrolidine instead of L-prolinol.

MS m/e (%): 646 (M+H⁺, 100)

Example 171(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 84% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (RS)-pyrrolidin-3-yl-methanol instead of L-prolinol.

MS m/e (%): 600 (M+H⁺, 100)

Example 1722-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 54% yieldafter flash chromatography according to the procedure described abovefor the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 4-(hydroxymethyl)piperidine instead of L-prolinol.

MS m/e (%): 594 (M+H⁺, 100)

Example 173(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy-propylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 30% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (R)-1-amino-2-propanol instead of L-prolinol.

MS m/e (%): 554 (M+H⁺, 100)

Example 174(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (S)-4-Benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine

A solution of 1.00 g (4.82 mmol) (R)-(4-benzyl-morpholin-3-yl)-methanol,0.80 g (5.3 mmol) tert-butyl-chloro-dimethyl-silane and 0.72 g (0.11mmol) imidazole in 10 ml N,N-dimethylformamide was stirred at roomtemperature for 90 min. Consecutive addition of water and 1 M aqueoussodium hydroxide solution was followed by extraction with three portionsof tert-butyl methyl ether. The combined organic layers were washed with1 M aqueous sodium hydroxide solution, dried over sodium sulphate andconcentrated in vacuo to give 1.54 g (99.3%) of the crude title compoundas a colorless oil.

MS m/e (%): 322 (M+H⁺, 100)

b) (S)-3-(tert-Butyl-dimethyl-silanyloxymethyl)-morpholine

A solution of 1.54 g (4.79 mmol)(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine in 24ml ethanol was deoxygenated by three cycles of evacuation and flushingwith argon. After addition of 0.5 g palladium on charcoal (10%) thereaction vessel was evacuated and filled with hydrogen gas. The reactionmixture was stirred at room temperature under an atmosphere of hydrogenover night. Filtration over decalite and evaporation of the solvent invacuo gave 1.08 g (97.4%) of the crude title compound as a colorlessoil.

MS m/e (%): 232 (M+H⁺, 100)

c)(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.30 g (0.56 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.17 g (0.73 mmol)(S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine, 0.01 g (0.03mmol) cetyltrimethylammonium bromide, 0.029 g (0.056 mmol)bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 3 ml toluenewas degassed by two freeze-thaw cycles. The reaction mixture was heatedunder argon at 90° C. for 3 h. After cooling to room temperature themixture was diluted with water and extracted with three portions oftoluene. The combined organic layers were dried over sodium sulphate andconcentrated in vacuo. The residue was dissolved in a mixture of 10 mlmethanol and 0.5 ml concentrated aqueous hydrochloric acid solution.After stirring at room temperature for 90 min. the reaction mixture wasneutralized with 0.5 M aqueous sodium hydroxide solution and extractedwith three portions of tert-butyl methyl ether. The combined organiclayers were dried over sodium sulfate and concentrated in vacuo. Flashcolumn chromatography gave 0.10 g (30%) of the title compound as anoff-white solid.

MS m/e (%): 614 (M+H⁺, 100)

Example 175(R)-(2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 61% yield afterflash chromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 596 (M+H⁺, 100)

Example 176(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (RS)-(4-benzyl-morpholin-2-yl)-methanol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 177(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (RS)-3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiomorpholine

The crude title compound was obtained as an orange oil in 92% yieldaccording to the procedure described above for the preparation of(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine using(RS)-thiomorpholin-3-yl-methanol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol.

MS m/e (%): 248 (M+H⁺, 100)

b)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 55% yield afterflash chromatography according to step c) of the procedure describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (RS)-3-(tert-butyl-dimethyl-silanyloxymethyl)-thiomorpholineinstead of (S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine.

MS m/e (%): 630 (M+H⁺, 100)

c)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 80% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 662 (M+H⁺, 100)

Example 178(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 644 (M+H⁺, 100)

Example 179(3R,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(3,5-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3R,5R)-1-benzyl-piperidine-3,5-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 180(3R,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3R,5R)-1-benzyl-piperidine-3,5-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 616 (M+H⁺, 100)

Example 181(3S,5R)-5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) (3R,5R)-1-Benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol

The title compound was obtained as a light brown oil in 38% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine using(3R,5R)-1-benzyl-piperidine-3,5-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol.

MS m/e (%): 322 (M+H⁺, 100)

b) (3S,5R)-1-Benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol

To a solution of 1.8 g (5.6 mmol)(3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50ml tetrahydrofuran were added at 0° C. 0.97 ml (6.2 mmol) diethylazodicarboxylate and 0.75 g (6.2 mmol) benzoic acid. The reactionmixture was cooled to 0° C., followed by addition of 1.6 g (6.2 mmol)triphenylphosphine. The reaction mixture was stirred at 0° C. for 6 h.Addition of a saturated sodium carbonate solution was followed byextraction with three portions of tert-butyl methyl ether. The combinedorganic layers were washed with saturated sodium carbonate solution andbrine, dried over sodium sulfate, concentrated in vacuo and purified byflash chromatography. The residue was dissolved in a mixture of 50 mldioxane and 18 ml 1 N aqueous sodium hydroxide solution. After stirringat 70° C. for 5 h the reaction mixture was diluted with tert-butylmethyl ether. The layers were separated and the organic layer was washedwith a saturation aqueous sodium carbonate solution. The combinedaqueous layers were extracted with two portions of tert-butyl methylether. The combined organic layers were washed with brine, dried oversodium sulfate and concentrated in vacuo. Flash chromatography gave 0.1g (6%) of the title compound as a light brown oil. MS m/e (%): 322(M+H⁺, 100)

c) (3S,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine

The title compound was obtained as a white solid in comparable yieldsaccording to the procedures described above for the preparation of(S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine using(3S,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-olinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a).

MS m/e (%): 346 (M+H⁺, 100)

d)(3S,5R)-5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldafter flash chromatography according to the procedure described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3S,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidineinstead of (S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 616 (M+H⁺, 100)

Example 182(3S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3,4-dihydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3S,4S)-1-benzyl-pyrrolidine-3,4-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 602 (M+H⁺, 100)

Example 183(3S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3S,4S)-1-benzyl-pyrrolidine-3,4-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 582 (M+H⁺, 100)

Example 184(3R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3,4-dihydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3R,4S)-3,4-dihydroxy-pyrrolidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 582 (M+H⁺, 100)

Example 185(3RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide using(3RS,4SR)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 186(3RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(3,4-dihydroxy-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3RS,4SR)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 187(3RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3RS,4SR)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 616 (M+H⁺, 100)

Example 188(3RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,4-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3RS,4SR)-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 616 (M+H⁺, 100)

Example 189(2RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and (2RS,4SR)-1-benzyl-2-hydroxymethyl-piperidin-4-ol insteadof (R)-(4-benzyl-morpholin-3-yl)-methanol in step a).(2RS,4SR)-1-Benzyl-2-hydroxymethyl-piperidin-4-ol is obtained byreduction of (1RS,5SR)-2-benzyl-6-oxa-2-aza-bicyclo[3.2.1]octan-7-onewith lithium aluminum hydride in tetrahydrofuran at room temperature for1 h.

MS m/e (%): 630 (M+H⁺, 100)

Example 190(2RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxy-2-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and (2RS,4SR)-1-benzyl-2-hydroxymethyl-piperidin-4-ol insteadof (R)-(4-benzyl-morpholin-3-yl)-methanol in step a).

MS m/e (%): 610 (M+H⁺, 100)

Example 191(3RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and 1-benzyl-3-hydroxymethyl-piperidin-4-ol as a mixture ofracemic diastereomers (Gueller, Rolf; Binggeli, Alfred; Breu, Volker;Bur, Daniel; Fischli, Walter; et al.; Bioorg. Med. Chem. Lett. 1999, 9,1403-1408.) instead of (R)-(4-benzyl-morpholin-3-yl)-methanol in stepa).(3RS,4SR)-1-Benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidinewas separated from(3RS,4RS)-1-benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidineby flash column chromatography and used in step b).

MS m/e (%): 610 (M+H⁺, 100)

Example 192(3RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxy-3-hydroxymethyl-4′-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and 1-benzyl-3-hydroxymethyl-piperidin-4-ol as a mixture ofracemic diastereomers (Gueller, Rolf; Binggeli, Alfred; Breu, Volker;Bur, Daniel; Fischli, Walter; et al.; Bioorg. Med. Chem. Lett. 1999, 9,1403-1408.) instead of (R)-(4-benzyl-morpholin-3-yl)-methanol in stepa).(3RS,4RS)-1-Benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidinewas separated from(3RS,4SR)-1-benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidineby flash column chromatography and used in step b).

MS m/e (%): 610 (M+H⁺, 100)

Example 193(3RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and 1-benzyl-3-hydroxymethyl-piperidin-4-ol as a mixture ofracemic diastereomers (Gueller, Rolf; Binggeli, Alfred; Breu, Volker;Bur, Daniel; Fischli, Walter; et al.; Bioorg. Med. Chem. Lett. 1999, 9,1403-1408.) instead of (R)-(4-benzyl-morpholin-3-yl)-methanol in stepa).(3RS,4SR)-1-Benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidinewas separated from(3RS,4RS)-1-benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidineby flash column chromatography and used in step b).

MS m/e (%): 630 (M+H⁺, 100)

Example 194(3RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and 1-benzyl-3-hydroxymethyl-piperidin-4-ol as a mixture ofracemic diastereomers (Gueller, Rolf; Binggeli, Alfred; Breu, Volker;Bur, Daniel; Fischli, Walter; et al.; Bioorg. Med. Chem. Lett. 1999, 9,1403-1408.) instead of (R)-(4-benzyl-morpholin-3-yl)-methanol in stepa).(3RS,4RS)-1-Benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidinewas separated from(3RS,4SR)-1-benzyl-4-(tert-butyl-dimethyl-silanyloxy)-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidineby flash column chromatography and used in step b).

MS m/e (%): 630 (M+H⁺, 100)

Example 195(2RS,3RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) (2RS,3RS)-3-Hydroxy-2-hydroxymethyl-piperidine-1-carboxylic AcidBenzyl Ester

A mixture of 20.0 g (105 mmol) 3-hydroxy-2-(hydroxymethyl)-pyridinehydrochloride, 4.0 g (18 mmol) platinum(IV) oxide, 4 g charcoal (NoritSX1) and 300 ml acetic acid was stirred at room temperature for 20 hunder a hydrogen pressure of 10 bar in an autoclave. The catalyst wasfiltered off and washed with acetic acid. The filtrate was concentratedin vacuo, redissolved in isopropanol and treated with 29.0 g (210 mmol)potassium carbonate. After stirring for 30 min. the mixture wasfiltered, and the solvent was evaporated in vacuo to give 15.7 g ofcrude (2RS,3RS)-2-hydroxymethyl-piperidin-3-ol. A portion of 2.0 g ofthe crude intermediate was dissolved in 50 ml dichloromethane andtreated with 5.2 ml (30 mmol) N,N-diisopropylethylamine and 2.4 ml (16mmol) benzyl chloroformate at 0° C. After 45 min. water and saturatedammonium chloride solution were added. The mixture was extracted withfour portions of dichloromethane. The combined organic layers were driedover sodium sulfate and concentrated in vacuo. Flash chromatography gave0.82 g (23% based on 3-hydroxy-2-(hydroxymethyl)-pyridine hydrochloride)of the title compound as an off-white oil.

MS m/e (%): 266 (M+H⁺, 92)

b)(2RS,3RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3-hydroxy-2-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c) and(2RS,3RS)-3-hydroxy-2-hydroxymethyl-piperidine-1-carboxylic acid benzylester instead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a).

MS m/e (%): 630 (M+H⁺, 100)

Example 1962-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(2-hydroxy-1-hydroxymethyl-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramidea)[2-(tert-Butyl-dimethyl-silanyloxy)-1-(tert-butyl-dimethyl-silanyloxymethyl)-ethyl]-methyl-amine

To 26 ml (0.21 mmol) of a 8 M solution of methylamine in ethanol wereadded dropwise at 0° C. 31 ml (0.11 mmol) titanium(IV) isopropoxide. Themixture was allowed to warm to room temperature over a period of 15 min.A solution of 17 g (0.52 mmol)1,3-bis-(tert-butyl-dimethyl-silanyloxy)-propan-2-one in 10 ml ethanolwas added. The reaction mixture was stirred at room temperature overnight, followed by addition of 6.6 g (0.11 mmol) sodiumcyanoborohydride. After stirring for 24 h the reaction was quenched bythe addition of silica gel. The mixture was concentrated in vacuo, andthe residue was transferred to a silica gel chromatography column. Flashchromatography and Kugelrohr distillation (120° C./2 mbar) gave 5.2 g(30%) of the title compound as a light yellow viscous oil.

MS m/e (%): 334 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-F(2-hydroxy-1-hydroxymethyl-ethyl)-methyl-amino1-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing[2-(tert-butyl-dimethyl-silanyloxy)-1-(tert-butyl-dimethyl-silanyloxymethyl)-ethyl]-methyl-amineinstead of (S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine instep c).

MS m/e (%): 602 (M+H⁺, 100)

Example 197(2R,5S)-N-[6-(2,5-Bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

and

Example 198(2S,5S)-N-[6-(2,5-Bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 0.30 g (0.56 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg(0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol)bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluenewas degassed by two freeze-thaw cycles. The reaction mixture was heatedunder argon at 90° C. over night. After cooling to room temperature themixture was diluted with water and extracted with three portions oftert-butyl methyl ether. The combined organic layers were dried oversodium sulphate and concentrated in vacuo. Flash column chromatographygave 0.09 g of the crude coupling product. This material was dissolvedin 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 Msolution of boron tribromide in dichloromethane at 0° C. After 15 min.the reaction was quenched by the addition of water, followed byextraction with three portions of dichloromethane. The combined organiclayers were dried over sodium sulphate and concentrated in vacuo. Flashcolumn chromatography gave 7 mg (2%) of(2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideas a light brown solid and 6 mg (2%) of(2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideas a light brown solid.

-   (2R,5S)-N-[6-(2,5-Bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

MS m/e (%): 628 (M+H⁺, 100)

-   (2S,5S)-N-[6-(2,5-Bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

MS m/e (%): 628 (M+H⁺, 100)

Example 199(2R,5R)-N-[6-(2,5-Bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of(2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideusing (2R,5R)-(+)-2,5-bis(methoxymethyl)pyrrolidine instead of(2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine.

MS m/e (%): 628 (M+H⁺, 100)

Example 200(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)(2S,4R)-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

A mixture of 26.5 g (71.8 mmol)(6-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester and25.4 g (144 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine in 260ml dimethyl sulfoxide was stirred at 130° C. for 32 h. The reactionmixture was concentrated in vacuo, treated with 200 ml 2 N sodiumcarbonate solution and extracted with three 200-ml portions of ethylacetate. The organic layers were washed with 200 ml 2 N sodium carbonatesolution and 200 ml brine and dried over sodium sulfate. Flashchromatography gave 15.5 g (48%) of the title compound as a white foam.

MS m/e (%): 450 (M+H⁺, 100)

b)(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 8.94 g (19.9 mmol)(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester in 85 ml dichloromethane were added 50 ml of a 2 Msolution of hydrogen chloride in diethylether at 0° C. The reactionmixture was stirred at room temperature for 22 h and concentrated invacuo. The residue was re-dissolved in 85 ml dichloromethane and treatedwith 17 ml (99.4 mmol) N-ethyldiisopropylamine. At 0° C. 19.0 g (59.7mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloridewere added dropwise. The reaction mixture was stirred at roomtemperature for 4 h and concentrated in vacuo. After addition of 250 mlmethanol and 70 ml 3 N potassium hydroxide solution the mixture wasstirred at room temperature for 2 h. The mixture was concentrated toremove methanol and extracted with four 750 ml-portions ofdichloromethane. The combined organic layers were washed with 500 ml 1 Nsodium hydroxide solution and 500 ml brine, dried over sodium sulfateand evaporated. Flash-chromatography gave 11 g (87%) of the titlecompound as a light yellow foam.

MS m/e (%): 632 (M+H⁺, 100)

c)(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 150 mg (0.238 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide,38.7 mg (0.284 mmol) 4-tolylboronic acid, 0.75 ml 2 N sodium carbonatesolution, 5.3 mg (0.024 mmol) palladium acetate and 12 mg (0.048 mmol)triphenylphosphine in 1.5 ml 1,2-dimethoxyethane was stirred at 80° C.for 2 h. The reaction mixture was treated with 10 ml 2 N sodiumcarbonate solution and extracted with two 15-ml portions of ethylacetate. The combined organic layers were dried over sodium sulfate andevaporated. Flash chromatography gave 112 mg (79%) of the title compoundas a yellow foam. MS m/e (%): 596 (M+H⁺, 100)

Example 201(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 72% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing phenylboronic acid instead of 4-tolylboronic acid in step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 202(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 62% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluorophenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 600 (M+H⁺, 100)

Example 203(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 41% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-chlorophenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 616 (M+H⁺, 100)

Example 204(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-dimethylamino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 76% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-dimethylaminophenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 625 (M+H⁺, 73)

Example 205(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 59% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-bromophenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 660 (M+H⁺, 45)

Example 206(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 68% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-chlorophenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 616 (M+H⁺, 100)

Example 207(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 97% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluorophenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 600 (M+H⁺, 100)

Example 208(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,5-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 74% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3,5-difluorophenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 618 (M+H⁺, 100)

Example 209(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a solid in 85% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3,4-difluorophenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 618 (M+H⁺, 100)

Example 210(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-4-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 60% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluoro-4-methylphenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 211(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 60% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-3-methylphenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 212(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 97% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-chloro-4-fluorophenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 634 (M+H⁺, 100)

Example 213(2S,4R)-N-[4-(2-Amino-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 82% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of4-tolylboronic acid in step c).

MS m/e (%): 597 (M+H⁺, 100)

Example 214(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 88% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-methoxyphenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 612 (M+H⁺, 100)

Example 215(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 61% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol instead of4-tolylboronic acid in step c).

MS m/e (%): 598 (M+H⁺, 100)

Example 216(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 79% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 4-tolylboronic acid in step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 217(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methylsulfanyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 86% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2-methylthio)phenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 628 (M+H⁺, 100)

Example 218(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methanesulfonyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 150 mg (0.239 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methylsulfanyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein 1.5 ml methanol were added 250 mg (0.406 mmol) potassiummonopersulfate triple salt. The reaction mixture was stirred at roomtemperature for 24 h. The reaction mixture was treated with 0.5 mlsodium hydrogen sulfite solution (38%) and stirred for 30 minutes.Addition of 5 ml 2 N sodium carbonate solution was followed byextraction with two 10-ml portions of dichloromethane. The combinedorganic layers were dried over sodium sulfate and purified by flashchromatography to give 131 mg (83%) of the title compound as a whitefoam. MS m/e (%): 660 (M+H⁺, 100)

Example 219(2S,4R)-2-[5-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-2-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-4-yl]-benzamide

The title compound was obtained as a light brown foam in 33% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2-aminocarbonyl)phenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 625 (M+H⁺, 100)

Example 220(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 78% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,4-difluorophenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 618 (M+H⁺, 100)

Example 221(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 76% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-chloro-4-fluorophenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 634 (M+H⁺, 100)

Example 222(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) 2-(2-Bromo-5-fluoro-phenyl)-1,3 dioxolane

To a solution of 2.0 g (9.9 mmol) 2-bromo-5-fluorobenzaldehyde in 20 mltoluene were added 0.722 ml (13.0 mmol) ethane-1,2-diol and 5 mg (0.03mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture washeated in a rotary evaporator at 60° C. and 200 mbar during 4 h. Afterevaporation of the solvent and flash chromatography 2.32 g (95%) of thetitle compound were obtained as a colorless liquid.

MS m/e (%): 246 (M⁺, 13)

b) 4-Fluoro-2-formylphenylboronic Acid

To a solution of 2.30 g (9.31 mmol)2-(2-bromo-5-fluoro-phenyl)-[1,3]dioxolane in 15 ml tetrahydrofuran wasadded dropwise at −70° C. 6.11 ml (9.77 mmol) of a 1.6 M solution ofn-butyllithium in hexane. The reaction mixture was stirred at −74° C.for 1 h. After dropwise addition of 2.65 ml (11.2 mmol) triisopropylborate at −70° C. the reaction mixture was allowed to warm to 15° C.during a period of 2 h. Water (7 ml) was added, and the mixture wasacidified to pH 1 by addition of 37% hydrochloric acid solution. Afterheating at 60° C. for 1 h, the mixture was cooled to room temperatureand extracted with three 50-ml portions of diethyl ether. The combinedorganic layers were washed with 50 ml brine, dried over sodium sulfateand concentrated. Flash chromatography gave 1.2 g (77%) of the titlecompound as a light yellow liquid.

MS m/e (%): 167 (M⁺, 1)

c)(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 80% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-formylphenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 628 (M+H⁺, 100)

Example 223(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 24 mg (0.637 mmol) sodium borohydride in 1 ml methanolwere added 100 mg (0.159 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideat room temperature. After stirring for 1 h the reaction mixture wasconcentrated in vacuo and partitioned between ethyl acetate andsaturated sodium carbonate solution. The layers were separated and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over sodium sulfate, concentrated in vacuo andpurified by flash chromatography to give 78 mg (78%) of the titlecompound as a white foam.

MS m/e (%): 630 (M+H⁺, 100)

Example 224(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 68% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-formylphenylboronic acid instead of 4-tolylboronic acid in stepc).

MS m/e (%): 610 (M+H⁺, 100)

Example 225(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-hydroxymethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 52% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 612 (M+H⁺, 100)

Example 226(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 60% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,5-dichlorophenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 650 (M+H⁺, 49)

Example 227(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 67% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 5-fluoro-2-methylphenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 228(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 100% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluoro-2-methylphenylboronic acid instead of 4-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 229(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 20% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,3-dichlorophenylboronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 650 (M+H⁺, 100)

Example 230(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,5-dimethyl-isoxazol-4-yl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 80% yield afterflash chromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3,5-dimethylisoxazole-4-boronic acid instead of 4-tolylboronicacid in step c).

MS m/e (%): 601 (M+H⁺, 100)

Example 231(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2,6-dimethoxy-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 67% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2,6-dimethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineinstead of 4-tolylboronic acid in step c).

MS m/e (%): 643 (M+H⁺, 100)

Example 232(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 49% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2-chloro-3-pyridyl)boronic acid instead of 4-tolylboronic acid instep c).

MS m/e (%): 617 (M+H⁺, 100)

Example 233(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

A mixture of 0.12 g (0.48 mmol) trifluoro-methanesulfonic acid2-methyl-pyridin-3-yl ester, 0.13 g (0.52 mmol) bis(pinacolato)diboron,0.14 g (1.4 mmol) potassium acetate and 0.02 g (0.02 mmol)dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II)dichloromethane adduct in 2.5 ml N,N-dimethylformamide was heated at 80°C. over night under argon. After cooling to room temperature 0.10 g(0.16 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideand 1.3 ml of a deoxygenated 2 M aqueous solution of sodium carbonatewere added. The reaction mixture was heated at 80° C. for 6 h. Aftercooling to room temperature the mixture was diluted with water andextracted with three portions of tert-butyl methyl ether. The combinedorganic layers were dried over sodium sulfate and concentrated in vacuo.Flash column chromatography gave 37 mg (39%) of the title compound as anoff-white solid.

MS m/e (%): 597 (M+H⁺, 100)

Example 234(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

To a solution of 0.500 g (2.09 mmol) 3-chloro-2-iodo-pyridine in 6 mltetrahydrofuran 1.04 ml (2.09 mmol) of a 2 M solution ofisopropylmagnesium chloride in tetrahydrofuran was added dropwise at−40° C. under an atmosphere of argon. After 30 min. 2.3 ml (4.2 mmol) ofan anhydrous 1.8 M solution of zinc chloride in tetrahydrofuran wasadded slowly. The cooling bath was removed after completed addition, andthe reaction mixture was stirred at room temperature for 90 min. Aportion of 1.6 ml of this solution was added to a solution of 0.15 g(0.24 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideand 14 mg (0.012 mmol) tetrakis(triphenylphosphine)palladium(0) in 1 mltetrahydrofuran. The mixture was heated at 100° C. under microwaveirradiation for 30 min. After cooling to room temperature a 0.5 Msolution of sodium hydroxide was added, and the mixture was extractedwith three portions of dichloromethane. The combined organic layers weredried over sodium sulfate and concentrated in vacuo. Flash columnchromatography gave 58 mg (40%) of the title compound as a light yellowsolid.

MS m/e (%): 617 (M+H⁺, 100)

Example 235(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(2S,4S)-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

The title compound was obtained as a light yellow foam in 60% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester using(2S,4S)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 450 (M+H⁺, 100)

b)(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 87% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideusing(2S,4S)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester instead of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester.

MS m/e (%): 632 (M+H⁺, 100)

c)(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 58% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-chloro-4-fluorophenylboronic acid instead of 4-tolylboronic acidand(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 634 (M+H⁺, 100)

Example 236(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 56% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,4-dichlorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 650 (M+H⁺, 100)

Example 237(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-difluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 78% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,4-difluorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 618 (M+H⁺,100)

Example 238(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 84% yield after flashchromatography according to the procedures described above for thepreparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-methylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 614 (M+H⁺,100)

Example 239(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 71% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-formylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 628 (M+H⁺,100)

Example 240(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 47% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 630 (M+H⁺, 100)

Example 241(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 90% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 2-chloro-4-fluorophenylboronic acidin step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 242(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 47% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-fluorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 600 (M+H⁺, 100)

Example 243(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 79% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-trifluoromethylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 650 (M+H⁺, 100)

Example 244(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 84% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-methoxyphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 612 (M+H⁺, 100)

Example 245(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-cyano-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 10% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileinstead of 2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 607 (M+H⁺, 100)

Example 246(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 68% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-bromophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 660 (M+H⁺, 100)

Example 247(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 80% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing phenylboronic acid instead of 2-chloro-4-fluorophenylboronic acidin step c).

MS m/e (%): 582 (M+H⁺, 100)

Example 248(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-3-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 92% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-3-methylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 249(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 87% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluoro-2-methylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 250(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 48% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 5-fluoro-2-methylphenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 251(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 87% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c).

MS m/e (%): 600 (M+H⁺, 100)

Example 252(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 64% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 3,4-dichlorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 650 (M+H⁺,100)

Example 253(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 77% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,3-dichlorophenylboronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 650 (M+H⁺,100)

Example 254(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 48% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (2-chloro-3-pyridyl)boronic acid instead of2-chloro-4-fluorophenylboronic acid in step c). MS m/e (%): 617 (M+H⁺,100)

Example 255(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 48% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramideusing(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 597 (M+H⁺, 100)

Example 256(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 24% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramideusing(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 617 (M+H⁺, 100)

Example 257(2R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)(2R,4R)-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

The title compound was obtained as a light brown foam in 28% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester using(2R,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 450 (M+H⁺, 100)

b)(2R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown foam in 82% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideusing(2R,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester instead of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester.

MS m/e (%): 632 (M+H⁺, 100)

c)(2R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 78% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 4-tolylboronic acid and(2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 596 (M+H⁺, 100)

Example 258(2R,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 85% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-methylphenylboronic acid instead of 2-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 259(2R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(2R,4S)-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

The title compound was obtained as a light brown foam in 14% yield afterflash chromatography according to the procedure described above for thepreparation of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester using(2R,4S)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 450 (M+H⁺, 100)

b)(2R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 71% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideusing(2R,4S)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester instead of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester.

MS m/e (%): 632 (M+H⁺, 100)

c)(2R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 78% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-methylphenylboronic acid instead of 4-tolylboronic acidand(2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 614 (M+H⁺, 100)

Example 260(2R,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 94% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 4-fluoro-2-methylphenylboronic acidin step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 261(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)(2R,3S)-[6-(3-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

The title compound was obtained as a light yellow foam in 29% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester using(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 450 (M+H⁺, 100)

b)(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 53% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideusing(2R,3S)-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester instead of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester.

MS m/e (%): 632 (M+H⁺, 100)

c)(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 85% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 4-tolylboronic acid and(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 596 (M+H⁺, 100)

Example 262(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 58% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(trifluoromethyl)phenylboronic acid instead of 2-tolylboronicacid in step c).

MS m/e (%): 650 (M+H⁺, 100)

Example 263(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 89% yield after flashchromatography according to the procedures described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-methoxyphenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 612 (M+H⁺, 100)

Example 264(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 70% yield after flashchromatography according to the procedures described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-fluorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 600 (M+H⁺, 100)

Example 265(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a brown foam in 79% yield after flashchromatography according to the procedures described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing phenylboronic acid instead of 2-tolylboronic acid in step c).

MS m/e (%): 582 (M+H⁺, 100)

Example 266(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 77% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 600 (M+H⁺, 100)

Example 267(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 53% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-tolylboronic acid instead of 2-tolylboronic acid in step c).

MS m/e (%): 596 (M+H⁺, 100)

Example 268(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 45% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3,4-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 650 (M+H⁺, 100)

Example 269(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 79% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-chlorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 616 (M+H⁺, 100)

Example 270(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 50% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,5 dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 650 (M+H⁺, 100)

Example 271(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 54% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,3-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 650 (M+H⁺, 100)

Example 272(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-4-fluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 77% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-chloro-4-fluorobenzeneboronic acid instead of 2-tolylboronicacid in step c).

MS m/e (%): 634 (M+H⁺, 100)

Example 273(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 60% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluoro-2-formylphenylboronic acid instead of 2-tolylboronic acidin step c).

MS m/e (%): 628 (M+H⁺, 100)

Example 274(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 48% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-hydroxymethyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-formyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 630 (M+H⁺, 100)

Example 275(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a off white foam in 78% yield afterflash chromatography according to the procedures described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3-fluoro-2-methylphenylboronic acid instead of 2-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 276(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(5-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 83% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 5-fluoro-2-methylphenylboronic acid instead of 2-tolylboronic acidin step c).

MS m/e (%): 614 (M+H⁺, 100)

Example 277(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,5-difluoro-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow foam in 52% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,5-difluorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 618 (M+H⁺, 100)

Example 278(2R,3S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 46% yieldafter flash chromatography according to the procedures described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramideusing(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 597 (M+H⁺, 100)

Example 279(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)(S)-[6-(2-Hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicAcid tert-butyl Ester

The title compound was obtained as a light yellow foam in 15% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester using L-prolinol instead of(2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine.

MS m/e (%): 434 (M+H⁺, 100)

b)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 74% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideusing(S)-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester instead of(2S,4R)-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-methyl-carbamicacid tert-butyl ester.

MS m/e (%): 616 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 43% yield after flashchromatography according to the procedure described above for thepreparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-p-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-tolylboronic acid instead of 4-tolylboronic acid and(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 580 (M+H⁺, 100)

Example 280(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-(2-methoxy-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 28% yield afterflash chromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-methoxyphenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 596 (M+H⁺, 100)

Example 281(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 23% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-bromophenylboronic acid instead of 2-tolylboronic acid in stepc). MS m/e (%): 644 (M+H⁺, 100)

Example 282(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 68% yield afterflash chromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2-fluorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 634 (M+H⁺, 100)

Example 283(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 29% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,4-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 634 (M+H⁺, 100)

Example 284(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,5-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow foam in 32% yield afterflash chromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,5-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 634 (M+H⁺, 100)

Example 285(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2,3-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 18% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 2,3-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 634 (M+H⁺, 100)

Example 286(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3,4-dichloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a orange foam in 34% yield afterflash chromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 3,4-dichlorophenylboronic acid instead of 2-tolylboronic acid instep c).

MS m/e (%): 634 (M+H⁺, 100)

Example 287(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a yellow oil in 50% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-chlorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 600 (M+H⁺, 100)

Example 288(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 45% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing 4-fluorophenylboronic acid instead of 2-tolylboronic acid in stepc).

MS m/e (%): 644 (M+H⁺, 100)

Example 289(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-phenyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 48% yield after flashchromatography according to the procedures described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing phenylboronic acid instead of 2-tolylboronic acid in step c).

MS m/e (%): 566 (M+H⁺, 100)

Example 290(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramidea) (6′-Chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine

The title compound was obtained as a light yellow solid in 60% yieldafter flash chromatography according to the procedure described abovefor the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramideusing (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine instead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramide.

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4]bipyridinyl-3′-yl)-N-methyl-isobutyramide

To a solution of 2.77 g (11.9 mmol)(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine in 120 mltetrahydrofuran 7.8 ml (12 mmol) of a 1.6 M solution of n-butyllithiumin hexanes was added dropwise at −78° C. After 30 min. 4.2 g (13 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride wereadded. The reaction mixture was stirred at −78° C. for 5 min. andallowed to warm to room temperature during a period of 1 h. Dilutionwith 2 M aqueous sodium carbonate solution was followed by extractionwith three portions of tert-butyl methyl ether. The combined organiclayers were washed with 2 M aqueous sodium carbonate solution and brine,dried over sodium sulfate and concentrated in vacuo. Flash columnchromatography gave 4.8 g (78%) of the title compound as an off-whitesolid.

MS m/e (%): 516 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-2-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 65% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 581 (M+H⁺, 100)

Example 291N-{6′-[Bis-(2-hydroxy-ethyl)-amino]-2-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 43% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 585 (M+H⁺, 100)

Example 292(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramidea) (6′-Chloro-4-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine

The title compound was obtained as a light yellow solid in comparableyield after flash chromatography according to the procedure describedabove for the preparation of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[3-chloro-6′-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-[2,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramideusing (6-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butylester instead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-iodo-pyridin-3-yl]-N-methyl-isobutyramideand 3-bromo-4-methylpyridine instead of 3-chloro-2-iodo-pyridine.

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6′-chloro-4-methyl-[3,4]bipyridinyl-3′-yl)-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 65% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideusing (6′-chloro-4-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine insteadof (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine.

MS m/e (%): 585 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6′-(2-hydroxymethyl-pyrrolidin-1-yl)-4-methyl-[3,4′]bipyridinyl-3′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 39% yieldafter flash chromatography according to the procedure described abovefor the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-4-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 581 (M+H⁺, 100)

Example 293N-{6′-[Bis-(2-hydroxy-ethyl)-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 34% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing diethanolamine instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-4-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 585 (M+H⁺, 100)

Example 2942-(3,5-Bis-trifluoromethyl-phenyl)-N-{6′-[(2-hydroxy-ethyl)-methyl-amino]-4-methyl-[3,4′]bipyridinyl-3′-yl}-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 66% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideusing 2-(methylamino) ethanol instead of ethanolamine and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-4-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 555 (M+H⁺, 100)

Example 295(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea) (2S,4R)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylEster

To a solution of 1.5 g (2.4 mmol)(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideand 0.4 ml (5 mmol) pyridine in 24 ml dichloromethane were addeddropwise at room temperature 0.22 ml (2.4 mmol) acetic anhydride. Afterstirring at room temperature for 20 h the reaction mixture was dilutedwith a 0.1 M aqueous hydrochloric acid solution and extracted with 3portions of dichloromethane. The combined organic extracts were washedwith a 2 M aqueous sodium carbonate solution, dried over sodium sulfateand concentrated in vacuo. Flash column chromatography gave 1.1 g (71%)of the title compound as an off-white solid.

MS m/e (%): 638 (M+H⁺, 100)

b) (S)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylEster

To a solution of 0.08 ml (0.9 mmol) oxalyl chloride in 2 mldichloromethane were added dropwise at −78° C. 0.13 ml (1.9 mmol)dimethyl sulfoxide and after a period of 3 min. a solution of 0.50 g(0.78 mmol) (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester in 2 ml dichloromethane. After stirring at −78° C. for 30 min. 0.7ml (4 mmol) N,N-diisopropylethylamine were added. The reaction mixturewas allowed to warm to room temperature during 1 h, diluted withtert-butyl methyl ether and washed with an aqueous ammonium chloridesolution. The aqueous layer was extracted with two portions oftert-butyl methyl ether. The combined organic extracts were dried oversodium sulfate and concentrated in vacuo. Flash column chromatographygave 0.47 g (94%) of the title compound as a white solid.

MS m/e (%): 636 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

A solution of 60 mg (0.094 mmol) (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester and a catalytic amount of sodium methylate in 2 ml methanol wasstirred at room temperature for 30 min. The reaction mixture was dilutedwith water and brine and extracted with three portions ofdichloromethane. The combined organic extracts were dried over sodiumsulfate and concentrated in vacuo. Flash column chromatography gave 13mg (23%) of the title compound as a light brown solid.

MS m/e (%): 594 (M+H⁺, 100)

Example 296(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (2S,4R)-Acetic Acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-hydroxy-pyrrolidin-2-ylmethylEster

The title compound was obtained as a white solid in 52% yield afterflash chromatography according to the procedure described above for thepreparation of (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester using(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 656 (M+H⁺, 100)

b) (S)-Acetic Acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-oxo-pyrrolidin-2-ylmethylEster

The title compound was obtained as a white solid in 77% yield afterflash chromatography according to the procedure described above for thepreparation of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester using (2S,4R)-acetic acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-hydroxy-pyrrolidin-2-ylmethylester instead of (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester.

MS m/e (%): 654 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in 37% yieldafter flash chromatography according to the procedure described abovefor the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-acetic acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-oxo-pyrrolidin-2-ylmethylester instead of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester.

MS m/e (%): 612 (M+H⁺, 100)

Example 297(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea) (2S,4S)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-fluoro-pyrrolidin-2-ylmethylEster

To a solution of 0.14 g (0.21 mmol) (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester in 2 ml dichloromethane were added dropwise at 0° C. 0.03 ml (0.2mmol) (diethylamino)sulfur trifluoride. After 1 h the reaction mixturewas diluted with a 0.5 M aqueous sodium hydroxide solution and extractedwith four portions of dichloromethane. The combined organic extractswere dried over sodium sulfate and concentrated in vacuo. Flash columnchromatography gave 47 mg (35%) of the title compound as a white solid.

MS m/e (%): 640 (M+H⁺, 100)

b)(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 91% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2S,4S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-fluoro-pyrrolidin-2-ylmethylester instead of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester.

MS m/e (%): 598 (M+H⁺, 100)

Example 298(2S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2S,4R)-acetic acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-hydroxy-pyrrolidin-2-ylmethylester instead of (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester in step a).

MS m/e (%): 616 (M+H⁺, 100)

Example 299(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea) (S)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4,4-difluoro-pyrrolidin-2-ylmethylEster

To a solution of 0.20 g (0.31 mmol) (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester in 3 ml dichloromethane were added at room temperature 0.19 ml(1.5 mmol) (diethylamino)sulfur trifluoride. After 36 h the reactionmixture was partitioned between water and tert-butyl methyl ether. Thelayers were separated and the organic layer was washed with 0.5 Maqueous sodium hydroxide solution. The combined aqueous layers wereextracted with three portions of tert-butyl methyl ether. The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo. Flash column chromatography gave 93 mg (45%) of the titlecompound as an off-white solid.

MS m/e (%): 658 (M+H⁺, 100)

b)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 83% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4,4-difluoro-pyrrolidin-2-ylmethylester instead of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester.

MS m/e (%): 616 (M+H⁺, 100)

Example 300(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-acetic acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-4-oxo-pyrrolidin-2-ylmethylester instead of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester in step a).

MS m/e (%): 634 (M+H⁺, 100)

Example 301(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea) (2S,4S)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylEster

The title compound was obtained as a white solid in 60% yield afterflash chromatography according to the procedure described above for thepreparation of (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester using(2S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideinstead of(2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 638 (M+H⁺, 100)

b) (2S,4R)-Acetic Acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-fluoro-pyrrolidin-2-ylmethylEster

The title compound was obtained as an off-white solid in 69% yield afterflash chromatography according to the procedure described above for thepreparation of (2S,4S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-fluoro-pyrrolidin-2-ylmethylester using (2S,4S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester instead of (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-hydroxy-pyrrolidin-2-ylmethylester.

MS m/e (%): 640 (M+H⁺, 100)

c)(2S,4R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-fluoro-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 78% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-4-oxo-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing (2S,4R)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-fluoro-pyrrolidin-2-ylmethylester instead of (S)-acetic acid1-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-4-oxo-pyrrolidin-2-ylmethylester.

MS m/e (%): 598 (M+H⁺, 100)

Example 302(S)-N-[6-[2-(Acetylamino-methyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidea)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.20 g (0.33 mmol)(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand 54 mg (0.37 mmol) phthalimide in 3 ml tetrahydrofuran were added 71mg (0.37 mmol) diethyl azodicarboxylate (90%) and 97 mg (0.37 mmol)triphenylphosphine at 0° C. After stirring for 90 min. the reactionmixture was allowed to warm to room temperature over night. The mixturewas diluted with a 0.1 M aqueous sodium hydroxide solution and extractedwith three portions of tert-butyl methyl ether. The combined organicextracts were dried over sodium sulphate and concentrated. Flash columnchromatography gave 70 mg (29%) of the title compound as a light yellowsolid.

MS m/e (%): 727 (M+H⁺, 100)

b)(S)-N-[6-[2-(Acetylamino-methyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A solution of 65 mg (0.089 mmol)(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 7.0 mg (0.14 mmol) hydrazine hydrate in 1 ml ethanol was stirred atroom temperature over night. The reaction mixture was diluted with a 1 Maqueous sodium hydroxide solution and extracted with three portions oftert-butyl methyl ether. The combined organic extracts were dried oversodium sulphate and concentrated to give 55 mg of crude(S)-N-[6-(2-aminomethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.This material was dissolved in 2 ml dichloromethane, followed by theaddition of 0.013 ml (0.092 mmol) triethylamine and 0.009 ml (0.09 mmol)acetic anhydride at 0° C. The cooling bath was removed 5 min. aftercompleted addition, and stirring was continued at room temperature overnight. The reaction mixture was diluted with a 0.5 M aqueous sodiumhydroxide solution and extracted with three portions of tert-butylmethyl ether. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash chromatography gave 44 mg (77%) of thetitle compound as an off-white solid.

MS m/e (%): 639 (M+H⁺, 100)

Example 303 (S)-Dimethyl-carbamic Acid1-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-yl]-pyrrolidin-2-ylmethylEster

To a solution of 44 mg (0.33 mmol) 1,1,3,3-tetramethyl-2-thiourea in 1.5ml N,N-dimethylformamide were added 0.027 ml iodomethane at roomtemperature. After stirring for 50 min. 0.20 g (0.33 mmol)(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand a suspension of 45 mg (0.90 mmol) sodium hydride (ca. 50% dispersionin mineral oil) in 0.5 ml n-hexane were added. After stirring at roomtemperature for 1 h the reaction mixture was diluted with water andextracted with three portions of tert-butyl methyl ether. The combinedorganic extracts were dried over sodium sulphate and concentrated. Flashcolumn chromatography gave 90 mg (40%) of the title compound as anoff-white solid.

MS m/e (%): 669 (M+H⁺, 100)

Example 304(3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) (5R,3S)-1-Benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol

To a solution of 1.8 g (5.6 mmol)(3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50ml THF were consecutively added 0.75 g (6.2 mmol) benzoic acid, 1.1 g(6.2 mmol) diethyl azodicarboxylate and 1.6 g (6.2 mmol)triphenylphosphine at 0° C. After 6 h the reaction mixture was dilutedwith tert-butyl methyl ether washed with a 2N aqueous solution of sodiumcarbonate. The aqueous layer was extracted with 3 portions of tert-butylmethyl ether. The combined organic extracts were washed with a 2Naqueous solution of sodium carbonate and brine and dried over sodiumsulfate. Flash chromatography gave 0.80 g (3S,5R)-benzoic acid1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-yl ester as alight brown oil. The ester was dissolved in a mixture of 50 ml dioxaneand 18 ml 1N aqueous sodium hydroxide solution. The reaction mixture washeated at 70° C. for 5 h. After cooling to room temperature the mixturewas extracted with tert-butyl methyl ether. The organic extract waswashed with a 2N aqueous solution of sodium carbonate. The combinedaqueous layers were extracted with two portions of tert-butyl methylether. The combined organic extracts were washed with brine and driedover sodium sulfate. Flash chromatography gave 0.10 g (17%) of the titlecompound as a light brown oil.

MS m/e (%): 322 (M+H⁺, 100)

b)(3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (5R,3S)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-olinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a).

MS m/e (%): 614.7 (M+H⁺, 100)

Example 305(3S,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) (3R,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine

The title compound was obtained as a light brown solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine (Example 174b))using (3R,5R)-1-benzyl-piperidine-3,5-diol instead of(R)-(4-benzyl-morpholin-3-yl)-methanol in step a).

MS m/e (%): 346 (M+H⁺, 100)

b)(3R,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylicAcid Benzyl Ester

To a solution of 0.50 g (1.4 mmol)(3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine and 0.15 g(1.5 mmol) triethylamine in 30 ml of THF was added dropwise a solutionof 0.26 g (1.5 mmol) benzyl chloroformate in 2 ml of THF at 0° C. Aftercompleted addition, the mixture was allowed to warm to room temperatureduring 30 min. Quenching with a saturated aqueous solution of sodiumhydrogencarbonate was followed by extraction with three portions ofdichloromethane. The combined organic extracts were washed with brineand dried over sodium sulfate. Flash chromatography gave 0.62 g (90%) ofthe title compound as a colorless oil.

MS m/e (%): 480 (M+H⁺, 100)

c)(3R,5R)-3-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylicAcid Benzyl Ester

To a solution of 8.7 g (18 mmol)(3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylicacid benzyl ester in 200 ml THF were added 18 ml (18 mmol) of a 1Msolution of tetrabutyl ammoniumfluoride in THF at 0° C. After completedaddition, the mixture was allowed to warm to room temperature overnight. Addition of water was followed by extraction with three portionsof tert-butyl methyl ether. The combined organic extracts were driedover sodium sulfate. Flash chromatography gave 1.1 g (16%) of the titlecompound as a pale yellow oil.

MS m/e (%): 366 (M+H⁺, 98)

d)(3S,5R)-3-Benzoyloxy-5-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylicAcid Benzyl Ester

To a solution of 2.8 g (7.8 mmol)(3R,5R)-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylicacid benzyl ester in 70 ml dry THF were consecutively added 1.0 g (8.5mmol) benzoic acid, 1.7 g (8.5 mmol) diethyl azodicarboxylate and 2.2 g(8.5 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixturewas diluted with tert-butyl methyl ether washed with a 2N aqueoussolution of sodium carbonate. The aqueous layer was extracted with 3portions of tert-butyl methyl ether. The combined organic extracts werewashed with a 2N aqueous solution of sodium carbonate and brine anddried over sodium sulfate. Flash chromatography gave 2.8 g (78%) of thetitle compound as a yellow oil. MS m/e (%): 470 (M+H⁺, 100)

e) (3S,5R)-3-Benzoyloxy-5-hydroxy-piperidine-1-carboxylic Acid BenzylEster

To a solution of 2.3 g (5.0 mmol)(3S,5R)-3-benzoyloxy-5-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylicacid benzyl ester in 20 ml dry THF were added 5.5 ml (5.5 mmol) of a 1Msolution of tetrabutyl ammoniumfluoride in THF at 0° C. After completedaddition, the mixture was allowed to warm to room temperature over 30min. Addition of water was followed by extraction with three portions oftert-butyl methyl ether. The combined organic extracts were dried oversodium sulfate. Kugelrohr distillation gave 1.7 g (95%) of the titlecompound as a light yellow oil.

MS m/e (%): 356 (M+H⁺, 100)

f) (3S,5S)-3,5-Dihydroxy-piperidine-1-carboxylic Acid Benzyl Ester

The title compound was obtained as a light brown oil in 4% yield afterflash chromatography according to the procedure described above for thepreparation of(5R,3S)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol(Example 304a)) using(3S,5R)-3-benzoyloxy-5-hydroxy-piperidine-1-carboxylic acid benzyl esterinstead of(3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol.

MS m/e (%): 252 (M+H⁺, 63)

g)(3S,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-3,5-dihydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-morpholin-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (3S,5S)-3,5-dihydroxy-piperidine-1-carboxylic acid benzyl esterinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 616 (M+H⁺, 100)

Example 306(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2-formyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a colorless viscous oil in comparableyields after flash chromatography according to the procedures describedabove for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 75a)) using(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 578 (M+H⁺, 100)

Example 307(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (S)-2-Methanesulfonylmethyl-pyrrolidine-1-carboxylic Acid BenzylEster

To a suspension of 1.81 g (25.8 mmol) sodium methanethiolate in 25 mlmethanol was added a solution of 1.35 g (4.31 mmol)2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid benzyl ester in25 ml methanol. Conversion was monitored by thin layer chromatography.After complete consumption of the starting material the reaction mixturewas diluted with ethyl acetate and washed with two portions of water.The organic layer was dried over sodium sulfate. Flash chromatographygave 0.89 g (3.4 mmol, 78%)(S)-2-methylsulfanylmethyl-pyrrolidine-1-carboxylic acid benzyl ester asa light yellow oil.

This material was dissolved in 25 ml of methanol and treated with 3.1 g(5.1 mmol) Oxone at room temperature. Conversion was monitored by thinlayer chromatography. After complete consumption of the startingmaterial the reaction mixture was diluted with water and extracted withthree portions of ethyl acetate. The combined organic extracts weredried over sodium sulfate and concentrated in vacuo to give 0.86 g (86%)of the crude title compound as a colorless oil.

MS m/e (%): 297 (M⁺, 3)

b) (S)-2-Methanesulfonylmethyl-pyrrolidine

A solution of 0.86 g (2.9 mmol)(S)-2-methanesulfonylmethyl-pyrrolidine-1-carboxylic acid benzyl esterin 15 ml ethanol was deoxygenated by three cycles of evacuation andflushing with argon. After addition of 0.15 g palladium on charcoal(10%) the reaction vessel was evacuated and filled with hydrogen gas.The reaction mixture was stirred at room temperature under an atmosphereof hydrogen over night. Filtration over decalite and evaporation of thesolvent in vacuo gave 0.44 g (93%) of the crude title compound as alight yellow oil.

MS m/e (%): 164 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid after preparativethin layer chromatography according to the procedure described above forthe preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (S)-2-methanesulfonylmethyl-pyrrolidine instead of L-prolinol.

MS m/e (%): 660 (M+H⁺, 100)

Example 3082-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

A mixture of 0.50 g (0.94 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.32 g (2.8 mmol) 4-(hydroxymethyl)piperidine, 0.12 g (2.8 mmol) lithiumchloride and 0.39 g (2.8 mmol) potassium carbonate in 5 ml DMSO washeated at 140° C. for 24 h. After cooling to room temperature thereaction mixture was diluted with water and extracted with threeportions of dichloromethane. The combined organic extracts were driedover sodium sulphate and concentrated. Flash column chromatography gave0.42 g (74%) of the title compound as a white solid.

MS m/e (%): 612 (M+H⁺, 100)

Example 3092-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) Methanesulfonic acid5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethylEster

To a solution of 0.42 g (0.69 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein 7 ml dichloromethane were added 83 mg (0.72 mmol) methanesulfonylchloride and 73 mg (0.72 mmol) triethylamine at 0° C. After 30 min thereaction mixture was diluted with water and extracted with threeportions of dichloromethane. The combined organic extracts were driedover sodium sulphate and concentrated. Flash column chromatography gave0.29 g (63%) of the title compound as a white solid.

MS m/e (%): 690 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

A solution of 0.29 g (0.42 mmol) methanesulfonic acid5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethylester and 44 mg (0.63 mmol) sodium methanethiolate in 8 ml DMF washeated at 80° C. for 30 min. After cooling to room temperature thereaction mixture was treated with a 1 N aqueous sodium hydroxidesolution and extracted with three portions of tert-butyl methyl ether.The combined organic extracts were dried over sodium sulphate andconcentrated. Flash column chromatography gave 0.25 g (92%) of the titlecompound as a white solid.

MS m/e (%): 642 (M+H⁺, 100)

Example 310(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

To a solution of 0.25 g (0.39 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein 10 ml dichloromethane were added 95 mg (70%, 0.39 mmol)3-chloroperbenzoic acid at 0° C. After completed addition, the reactionmixture was allowed to warm to room temperature and stirred over night.An aqueous solution of sodium hydrogensulfite was added and the mixturewas stirred for 10 min. Basification with 1 N aqueous sodium hydroxidesolution was followed by extraction with three portions ofdichloromethane. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash column chromatography gave 0.23 g (89%)of the title compound as a white solid.

MS m/e (%): 658 (M+H⁺, 100)

Example 3112-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

To a solution of 0.22 g (0.33 mmol)(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein 5 ml dichloromethane were added 142 mg (70%, 0.58 mmol)3-chloroperbenzoic acid at 0° C. After completed addition, the reactionmixture was allowed to warm to room temperature and stirred over night.An aqueous solution of sodium hydrogensulfite was added and the mixturewas stirred for 10 min. Basification with 1 N aqueous sodium hydroxidesolution was followed by extraction with three portions ofdichloromethane. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash column chromatography gave 0.13 g (55%)of the title compound as a white solid.

MS m/e (%): 674 (M+H⁺, 100)

Example 312(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 70% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing (RS)-3-(hydroxymethyl)pyrrolidine instead of4-(hydroxymethyl)piperidine.

MS m/e (%): 598 (M+H⁺, 100)

Example 313(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 66% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 628 (M+H⁺, 100)

Example 3142-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(RS)-3-((RS)-methanesulfinylmethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide

The title compound was obtained as a white solid in 86% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 644 (M+H⁺, 100)

Example 315(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylmethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 31% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[(RS)-3-((RS)-methanesulfinylmethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 660 (M+H⁺, 100)

Example 316(R)-N-[6-(3-Amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 939 mg (1.76 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,1.22 g (8.81 mmol) potassium carbonate and 770 mg (3.52 mmol)(R)-3-(trifluoro-acetamido)pyrrolidine hydrochloride in 20 ml dimethylsulfoxide was stirred at 130° C. for 52 h. After cooling to roomtemperature the reaction mixture was diluted with 30 ml tert-butylmethyl ether and washed with 20 ml of water and 10 ml of a saturatedaqueous solution of sodium carbonate. The combined organic layers weredried over sodium sulfate, concentrated and dissolved in 25 ml of a 2 Nsolution of ammonia in ethanol. The solution was stirred at roomtemperature for 18 h. The reaction mixture was concentrated and purifiedby flash chromatography to give 670 mg (65%) of the title compound as alight brown foam.

MS m/e (%): 583 (M+H⁺, 100)

Example 317(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 620 mg (1.06 mmol)(R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 6 ml dichloromethane were added 7 mg (0.05 mmol)4-(N,N-dimethylamino)pyridine, 275 mg (2.13 mmol)N,N-diisopropylethylamine and 158 mg (1.38 mmol) methanesulfonylchloride at room temperature. After stirring for 18 h the reactionmixture was diluted with 20 ml dichloromethane and washed with 20 ml ofa saturated aqueous solution of sodium carbonate. The combined organiclayers were dried over sodium sulfate, concentrated and purified byflash chromatography to give 618 mg (88%) of the title compound as anoff-white foam.

MS m/e (%): 659 (M+H⁺, 66)

Example 318(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramide

To a solution of 150 mg (0.227 mmol)(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein 1 ml dimethylformamide were added 15 mg (0.34 mmol) sodium hydride(55% dispersion in mineral oil) at room temperature. After stirring atroom temperature for 30 min 39 mg (27 mmol) iodomethane were added. Thereaction mixture was stirred at room temperature for 18 h, followed bydilution with 10 ml ethyl acetate and washing with 10 ml saturatedsodium carbonate solution. The combined organic layers were dried oversodium sulfate, concentrated in vacuo and purified by flashchromatography to give 120 mg (78%) of the title compound as a whitefoam.

MS m/e (%): 675 (M+H⁺, 100)

Example 319(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[3-(ethyl-methanesulfonyl-amino)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 84% yield after flashchromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramideusing iodoethane instead of iodomethane.

MS m/e (%): 689 (M+H⁺, 100)

Example 3202-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 93% yield after flashchromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusingN-[4-amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide(Example 114c)) instead of(R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 673 ([M−H⁺]⁻, 90)

Example 3212-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-(methanesulfonyl-methyl-amino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 98% yield after flashchromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 689 (M+H⁺, 100)

Example 3222-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(ethyl-methanesulfonyl-amino)-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 95% yield after flashchromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-2-methyl-phenyl)-6-[3-(methanesulfonyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand iodoethane instead of iodomethane.

MS m/e (%): 703 (M+H⁺, 100)

Example 3232-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

A mixture of 150 mg (0.28 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 0.16 g (0.84 mmol) 4-(trifluoromethyl)piperidine hydrochloride in 2ml 1,8-diazabicyclo[5.4.0]undec-7-ene was heated at 140° C. for 20 h.After cooling to room temperature the reaction mixture was diluted withwater and extracted with three portions of tert-butyl methyl ether. Thecombined organic layers were dried over sodium sulfate, concentrated invacuo and purified by flash chromatography to give 62 mg (34%) of thetitle compound as a light yellow solid.

MS m/e (%): 650 (M+H⁺, 100)

Example 3242-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 38% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 309) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 162) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 600 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.25 g (0.42 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein 10 ml dichloromethane were added 206 mg (70%, 0.84 mmol)3-chloroperbenzoic acid at 0° C. After completed addition, the reactionmixture was allowed to warm to room temperature and stirred for 2 h. Anaqueous solution of sodium hydrogensulfite was added and the mixture wasstirred for 10 min. Basification with 1 N aqueous sodium hydroxidesolution was followed by extraction with three portions ofdichloromethane. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash column chromatography gave 0.16 g (60%)of the title compound as a white solid.

MS m/e (%): 632 (M+H⁺, 100)

Example 325(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 60% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing (RS)-3-hydroxypiperidine instead of 4-(hydroxymethyl)piperidine.

MS m/e (%): 598 (M+H⁺, 100)

b)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 5% yield after flashchromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 324) using(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 660 (M+H⁺, 100)

Example 3262-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 35% yield afterflash column chromatography according to the procedures described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 114a)) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 660 (M+H⁺, 100)

Example 327(1S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 57% yieldafter flash chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing nortropine instead of 4-(hydroxymethyl)piperidine.

MS m/e (%): 624 (M+H⁺, 100)

Example 328(1R,3S,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 37% yield afterflash chromatography according to the procedure described above for thepreparation of(5R,3S)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol(Example 304a)) using(1S,3R,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol.

MS m/e (%): 624 (M+H⁺, 100)

Example 329(rac)-(1R,3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfinyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(1R,3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 45% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing(1R,3S,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 654 (M+H⁺, 100)

b)(rac)-(1R,3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfinyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 78% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing(1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 670 (M+H⁺, 100)

Example 330(1R,3R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 60% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing(rac)-(1R,3R,5S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfinyl-8-aza-bicyclo[3.2.1]oct-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 686 (M+H⁺, 100)

Example 3312-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-dimethylsulfamoyl-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidea) Thioacetic acid5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylEster

A solution of 0.22 g (0.84 mmol) triphenylphosphine and 0.15 g (0.84mmol) diethyl azodicarboxylate in 3.33 ml THF was stirred for 15 min at0° C. This solution was added to a solution of 0.25 g (0.42 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideand 64 mg (0.84 mmol) thioacetic acid in 10 ml THF at 0° C. Conversionwas monitored by thin layer chromatography. After complete consumptionof the starting material a 2 N aqueous solution of sodium carbonate wasadded. The mixture was extracted with three portions of tert-butylmethyl ether. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash column chromatography gave 0.16 g (59%)of the title compound as a white solid.

MS m/e (%): 656 (M+H⁺, 100)

b)5′-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-sulfonicAcid

To a suspension of 0.16 g (0.24 mmol) thioacetic acid5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylester in 1 ml acetic acid were added 0.12 ml (1.2 mmol) of a 30% aqueoussolution of hydrogen peroxide at room temperature. After heating to 60°C., a clear solution was obtained. Stirring was continued at thistemperature for 20 h. After cooling to room temperature an aqueoussolution of sodium hydrogensulfite was added and the mixture was stirredfor 10 min. Acidification with 1 N aqueous hydrochloride solution to pH1 was followed by extraction with three portions of dichloromethane. Thecombined organic extracts were dried over sodium sulphate andconcentrated. Flash column chromatography gave 0.13 g (83%) of the titlecompound as a light yellow solid.

MS m/e (%): 660 ([M−H⁺]⁻, 100)

c)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-dimethylsulfamoyl-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

To a solution of 0.13 g (0.19 mmol)5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-sulfonicacid in 2 ml dichloromethane were added 0.33 ml (0.39 mmol) oxalylchloride and one drop of DMF at 0° C. After 30 min the reaction mixturewas allowed to warm to room temperature during 2 h. To the yellowreaction mixture were added 1.8 ml (20 mmol) of an aqueous solution ofdimethylamine (60%). After 1 h the reaction mixture was diluted withwater and extracted with three portions of dichloromethane. The combinedorganic extracts were dried over sodium sulphate and concentrated. Flashcolumn chromatography gave 92 mg (69%) of the title compound as a whitesolid.

MS m/e (%): 689 (M+H⁺, 100)

Example 3322-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methylsulfanyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 59% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 51) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 630 (M+H⁺, 100)

Example 333(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfinyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 84% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methylsulfanyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methylsulfanylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 646 (M+H⁺, 100)

Example 3342-(3,5-Bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 86% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfonylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-methanesulfinyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide.

MS m/e (%): 662 (M+H⁺, 100)

Example 3352-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.20 g (0.34 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramidein 5 ml dichloromethane were added 0.03 g (0.4 mmol) 2-mercaptoethanoland 0.11 g (0.34 mmol) boron trifluoride etherate at 0° C. After 1 h thereaction mixture was allowed to warm to room temperature and stirredover night. Dilution with a 2 N aqueous sodium hydroxide solution wasfollowed by extraction with 3 portions of dichloromethane. The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo. Flash column chromatography gave 0.22 g (98%) of the titlecompound as a white solid.

MS m/e (%): 656 (M+H⁺, 100)

Example 3362-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4,4-dioxo-1-oxa-4λ⁶-thia-8-aza-spiro[4.5]dec-8-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 55% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 688 (M+H⁺, 100)

Example 3372-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-5-thia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 84% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 3-mercapto-1-propanol instead of 2-mercaptoethanol.

MS m/e (%): 670 (M+H⁺, 100)

Example 3382-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(5,5-dioxo-1-oxa-5λ⁶-thia-9-aza-spiro[5.5]undec-9-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 70% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-5-thia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 702 (M+H⁺, 100)

Example 3392-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,4,4-tetraoxo-1λ⁶,4λ⁶-dithia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,4-dithia-8-aza-spiro[4.5]dec-8-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 41% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 1,2-ethanedithiol instead of 2-mercaptoethanol.

MS m/e (%): 672 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,4,4-tetraoxo-1λ⁶,4λ⁶-dithia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 33% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,4-dithia-8-aza-spiro[4.5]dec-8-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand 4 instead of 2 equivalents of 3-chloroperbenzoic acid.

MS m/e (%): 736 (M+H⁺, 100)

Example 3402-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,5,5-tetraoxo-1λ⁶,5λ⁶-dithia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,5-dithia-9-aza-spiro[5.5]undec-9-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 41% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-4-thia-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 1,3-propanedithiol instead of 2-mercaptoethanol.

MS m/e (%): 686 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1,1,5,5-tetraoxo-1λ⁶,5λ⁶-dithia-9-aza-spiro[5.5]undec-9-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 4% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,5-dithia-9-aza-spiro[5.5]undec-9-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideand 4 instead of 2 equivalents of 3-chloroperbenzoic acid.

MS m/e (%): 750 (M+H⁺, 100)

Example 3412-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 12% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing 1-oxa-8-azaspiro[4.5]decane trifluoroacetic acid salt instead of4-(trifluoromethyl)piperidine hydrochloride.

MS m/e (%): 638 (M+H⁺, 100)

Example 342(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.10 g (0.17 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 142), 12 mg (0.39 mmol) paraformaldehyde and 61 mg (0.51 mmol)magnesium sulfate in 2 ml 1,2-dichloromethane was heated at 85° C. untilcomplete consumption of starting material. After cooling to roomtemperature the reaction mixture was diluted with water and extractedwith 3 portions of tert-butyl methyl ether. The combined organicextracts were dried over sodium sulfate and concentrated in vacuo. Flashcolumn chromatography gave 60 mg (59%) of the title compound as anoff-white solid.

MS m/e (%): 600 (M+H⁺, 100)

Example 3432-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 67% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide(Example 115) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand morpholine instead of 2-(methylamino)ethanol.

MS m/e (%): 584 (M+H⁺, 100)

Example 3442-(3,5-Bis-trifluoromethyl-phenyl)-N-[(1S,5R)-4-(4-fluoro-2-methyl-phenyl)-6-8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.15 g (0.28 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.13 g (0.84 mmol) 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride and0.20 g (1.4 mmol) potassium carbonate in 1 ml dimethyl sulfoxide washeated at 150° C. under microwave irradiation in a sealed tube for 30min. Another portion of 0.06 g (0.4 mmol)8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride was added and thereaction mixture was heated at 150° C. under microwave irradiation in asealed tube for 30 more minutes. After cooling to room temperature thereaction mixture was diluted with water and extracted with four portionsof tert-butyl methyl ether. The combined organic extracts were driedover sodium sulfate and concentrated. Flash column chromatography gave32 mg (18%) of the title compound as a light yellow solid.

MS m/e (%): 610 (M+H⁺, 100)

Example 3452-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as light orange foam in 19% yield afterflash chromatography according to the procedure described above for thepreparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 155) using 2-(methylthio)ethylamine instead of(2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 588 (M+H⁺, 100)

Example 3462-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 54% yield after flashchromatography according to the procedure described above for thepreparation of (S)-2-methanesulfonylmethyl-pyrrolidine-1-carboxylic acidbenzyl ester (Example 307a)) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideinstead of (S)-2-methylsulfanylmethyl-pyrrolidine-1-carboxylic acidbenzyl ester.

MS m/e (%): 620 (M+H⁺, 100)

Example 3472-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiazolidin-3-yl-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.25 g (0.47 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 0.59 g (6.6 mmol) thiazolidine was heated three times at 180° C. for30 minutes and once at 250° C. for 15 minutes under microwaveirradiation in a sealed tube. The reaction mixture was diluted with a0.2 M aqueous solution of sodium hydroxide and extracted with threeportions of tert-butyl methyl ether. The combined organic extracts weredried over sodium sulfate and concentrated in vacuo. Flash columnchromatography and drying in high vacuo (70-90° C./1-2 mbar) for threehours gave 33 mg (12%) of the title compound as a yellow oil.

MS m/e (%): 586 (M+H⁺, 100)

Example 348 (1RS,4RS)- or(1RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Diastereomeric Racemate of Example 349)

and

Example 349 (1RS,4SR)- or(1RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Diastereomeric Racemate of Example 348) a)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 42% yield afterflash chromatography according to the procedure described above for thepreparation of(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine(Example 174a)) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 142) instead of (R)-(4-benzyl-morpholin-3-yl)-methanol.

MS m/e (%): 702 (M+H⁺, 100)

b) (RS)-Thioacetic Acid2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3-(tert-butyl-dimethyl-silanyloxy)-propylEster

To a solution of 0.19 mg (0.71 mmol) triphenylphosphine in 10 ml dry THFwere added 0.12 g (0.71 mmol) diethyl azodicarboxylate at 0° C. underargon. After 30 min a solution of 0.50 g (0.71 mmol)(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein 5 ml dry THF and 0.06 g (0.9 mmol) thioacetic acid were added. Thereaction mixture was allowed to warm to room temperature over night.Dilution with a saturated aqueous solution of sodium hydrogencarbonatewas followed by extraction with three portions of tert-butyl methylether. The combined organic extracts were dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography gave 0.28 g (52%) ofthe title compound as a white solid. MS m/e (%): 760 (M+H⁺, 100)

c)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-mercaptomethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.28 mg (0.37 mmol) (RS)-thioacetic acid2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3-(tert-butyl-dimethyl-silanyloxy)-propylester in 10 ml ethanol and 4 ml of a 2 N solution of ammonia in ethanolwas heated at reflux for 4 h. After cooling to room temperature thereaction mixture was concentrated in vacuo to give 0.22 g of the crudetitle compound as a light brown amorphous residue, which was used in thenext step without any further purification.

d)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-mercaptomethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The crude title compound was obtained as a light brown amorphous residuein quantitative yield after extraction according to the proceduredescribed above for the preparation of(S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine(Example 174a)) using(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-mercaptomethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideinstead of (R)-(4-benzyl-morpholin-3-yl)-methanol.

e)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-thiazolidin-3-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 39% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 342) using(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-mercaptomethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 730 (M+H⁺, 100)

f)(1RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramideand(1RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 50 mg (0.069 mmol)(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-thiazolidin-3-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein 2 ml dichloromethane were added 17 mg (70%, 0.069 mmol)3-chloroperbenzoic acid at 0° C. After completed addition, the reactionmixture was allowed to warm to room temperature during 3 h. A saturatedaqueous solution of sodium carbonate was added and the mixture wasextracted with three portions of dichloromethane. The combined organicextracts were dried over sodium sulphate and concentrated. The residue,80 mg of a brown oil, was dissolved in 2 ml THF and treated with 0.07 ml(0.07 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF atroom temperature. After stirring at room temperature over night thereaction mixture was diluted with a 2 N aqueous solution of sodiumcarbonate and extracted with three portions of tert-butyl methyl ether.The combined organic extracts were dried over sodium sulphate andconcentrated. Preparative thin layer chromatography gave 24 mg (55%) ofone diastereomeric racemate of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramideas a white solid and 11 mg (25%) of the second diastereomeric racemateof2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramideas a white solid. The assignment of the relative configuration of thetwo diastereomeric racemates was not possible.

(1RS,4RS)- or(1RS,4SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 632 (M+H⁺, 100)

(1RS,4SR)- or(1RS,4RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 632 (M+H⁺, 100)

Example 350(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1,1-dioxo-1λ⁶-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 83% yield from(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-thiazolidin-3-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideafter flash chromatography according to the procedure described abovefor the preparation of(1RS,4RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramideand(1RS,4SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-1-oxo-1λ⁴-thiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(step f)) using two instead of one molar equivalents of3-chloroperbenzoic acid.

MS m/e (%): 648 (M+H⁺, 100)

Example 351(1S,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(8,8-dioxo-8λ⁶-thia-3-aza-bicyclo[3.2.1]oct-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidea)(1S,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-8-thia-3-aza-bicyclo[3.2.1]oct-3-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light yellow viscous oil in 22%yield after flash chromatography according to the procedure describedabove for the preparation of(2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 155) using (1S,5R)-8-thia-3-azabicyclo[3.2.1]octanehydrochloride instead of (2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine.

MS m/e (%): 626 (M+H⁺, 100)

b)(1S,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(8,8-dioxo-8λ⁶-thia-3-aza-bicyclo[3.2.1]oct-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 42% yield afterflash chromatography according to the procedure described above for thepreparation of (S)-2-methanesulfonylmethyl-pyrrolidine-1-carboxylic acidbenzyl ester (Example 307a)) using(1S,5R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-8-thia-3-aza-bicyclo[3.2.1]oct-3-yl-pyridin-3-yl]-N-methyl-isobutyramideinstead of (S)-2-methylsulfanylmethyl-pyrrolidine-1-carboxylic acidbenzyl ester.

MS m/e (%): 658 (M+H⁺, 100)

Example 352(+)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid by preparative HPLCseparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 178) on a Chiralpak AD column (heptane/ethanol 85:15).

MS m/e (%): 644 (M+H⁺, 100)

Example 353(−)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in 81% enantiomeric excess as a whitesolid by preparative HPLC separation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 178) on a Chiralpak AD column (heptane/ethanol 85:15).

MS m/e (%): 644 (M+H⁺, 100)

Example 354(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideand Example 3552-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[1,4]thiazepan-4-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 41% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 323) using [1,4]thiazepane hydrochloride instead of4-(trifluoromethyl)piperidine hydrochloride.

MS m/e (%): 614 (M+H⁺, 100)

b)(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideand2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.11 g (0.18 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[1,4]thiazepan-4-yl-pyridin-3-yl]-N-methyl-isobutyramidein 2 ml dichloromethane were added 63 mg (70%, 0.27 mmol)3-chloroperbenzoic acid at room temperature. The reaction mixture wasstirred over night. Dilution with a 2 M aqueous solution of sodiumcarbonate was followed by extraction with three portions ofdichloromethane. The combined organic extracts were dried over sodiumsulphate and concentrated. Flash column chromatography gave 71 mg (66%)of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramideas a white solid and 32 mg (29%) of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideas a white solid.

(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(1-oxo-1λ⁴-[1,4]thiazepan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 630 (M+H⁺, 100)

2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-λ⁶-[1,4]thiazepan-4-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide:MS m/e (%): 646 (M+H⁺, 100)

Example 3562-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,3]thiazinan-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 2.0 g (3.8 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 5.6 g (75 mmol) 3-amino-1-propanol was heated at 180° C. undermicrowave irradiation for 40 min. Dilution with water was followed byextraction with three portions of tert-butyl methyl ether. The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo. Flash chromatography gave 1.9 g (87%) of the title compound as awhite solid.

MS m/e (%): 572 (M+H⁺, 100)

b) Thioacetic Acid3-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-propylEster

The title compound was obtained as a white solid in 69% yield afterflash chromatography according to the procedure described above for thepreparation of (RS)-thioacetic acid2-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-3-(tert-butyl-dimethyl-silanyloxy)-propylester (Example 349b)) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramideinstead of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-ethylamino]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 630 (M+H⁺, 100)

c)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-mercapto-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 1.3 g (2.0 mmol) thioacetic acid3-[5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-2-methyl-phenyl)-pyridin-2-ylamino]-propylester in 20 ml methanol were added 5 ml of a 25% aqueous solution ofammonium hydroxide. The reaction mixture was heated at 50° C. for 1 h.After cooling to room temperature the mixture was acidified with 1 Naqueous hydrochloric acid solution and extracted with three portions oftert-butyl methyl ether. The combined organic layers were dried oversodium sulfate and concentrated in vacuo to give the crude titlecompound in quantitative yield as a light yellow solid.

MS m/e (%): 588 (M+H⁺, 100)

d)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[1,3]thiazinan-3-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 68% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 342) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-mercapto-propylamino)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 600 (M+H⁺, 100)

e)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ⁶-[1,3]thiazinan-3-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 73% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 324b)) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-[1,3]thiazinan-3-yl-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methylsulfanyl-azetidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 632 (M+H⁺, 100)

Example 357N-[6-(2-Amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 1.0 g (1.9 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand 5.0 ml (75 mmol) ethylenediamine was heated at 130° C. for 6 h.After cooling to room temperature the reaction mixture was diluted with20 ml tert-butyl methyl ether and washed with 20 ml of a saturatedaqueous solution of sodium carbonate, 20 ml of water and 20 ml of asaturated aqueous solution of sodium carbonate. The combined organiclayers were dried over sodium sulfate, concentrated in vacuo andpurified by flash chromatography to give 0.92 g (88%) of the titlecompound as a white foam.

MS m/e (%): 557 (M+H⁺, 100)

Example 3582-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methanesulfonylamino-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 89% yield after flashchromatography according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 317) usingN-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(R)-N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 633 ([M−H⁺]⁻, 74)

Example 3592-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonyl-imidazolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.20 g (0.36 mmol)N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 2 ml 1,2-dichloroethane were added 42 mg (0.48 mmol) paraformaldehydeand 0.13 g (1.1 mmol) magnesium sulfate. After stirring at roomtemperature for 18 h 0.14 g (1.1 mmol) N,N-diisopropylethylamine, 2 mg(0.02 mmol) 4-(N,N-dimethylamino)pyridine and 62 mg (0.54 mmol)methanesulfonyl chloride were added. The reaction mixture was heated to80° C. and kept at this temperature for 4 h. After cooling to roomtemperature the reaction mixture was diluted with 20 ml tert-butylmethyl ether and washed with two 20-ml portions of a saturated aqueoussolution of sodium carbonate. The combined organic layers were driedover sodium sulfate, concentrated in vacuo and purified by flashchromatography to give 93 mg (40%) of the title compound as a whitefoam.

MS m/e (%): 647 (M+H⁺, 100)

Example 360N-[6-(2-Acetylamino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 48% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 356a)) using N-acetylethylenediamine instead of3-amino-1-propanol.

MS m/e (%): 599 (M+H⁺, 100)

Example 361N-[6-(3-Acetyl-imidazolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

To a solution of 50 mg (0.090 mmol)N-[6-(2-amino-ethylamino)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 2 ml 1,2-dichloroethane were added 3 mg (0.1 mmol) paraformaldehydeand 32 mg (0.27 mmol) magnesium sulfate. After stirring at roomtemperature over night another 3 mg (0.1 mmol) paraformaldehyde wereadded and the reaction mixture was heated to 85° C. After 1 h thereaction mixture was cooled to room temperature and treated with 14 mg(0.13 mmol) triethylamine and 11 mg (0.13 mmol) acetyl chloride.Conversion was monitored by thin layer chromatography. After completeconsumption of the starting material the reaction mixture was dilutedwith water and extracted with three portions of dichloromethane. Thecombined organic layers were dried over sodium sulfate, concentrated invacuo and purified by flash chromatography to give 40 mg (73%) of thetitle compound as an off-white solid.

MS m/e (%): 611 (M+H⁺, 100)

Example 3622-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide

The crude title compound was obtained as an off-white solid in 98% yieldafter extraction according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-N-methyl-isobutyramide(Example 115) using2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand piperazine instead of 2-(methylamino)ethanol.

MS m/e (%): 565 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.16 g (0.31 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramideand 38 mg (0.38 mmol) triethylamine in 4 ml dichloromethane were added38 mg (0.33 mmol) methanesulfonyl chloride at 0° C. After completedaddition the reaction mixture was allowed to warm to room temperature.Conversion was monitored by thin layer chromatography. After completeconsumption of the starting material the reaction mixture was dilutedwith water and extracted with three portions of tert-butyl methyl ether.The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography gave 0.15 g (75%) ofthe title compound as a white solid.

MS m/e (%): 643 (M+H⁺, 100)

Example 3632-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 73% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a).

MS m/e (%): 663 (M+H⁺, 100)

Example 3642-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-chloro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 79% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-chloro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4K) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a).

MS m/e (%): 677 (M+H⁺, 100)

Example 3652-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(3-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 77% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4E) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a).

MS m/e (%): 661 (M+H⁺, 100)

Example 3662-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 83% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4D) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a).

MS m/e (%): 661 (M+H⁺, 100)

Example 3672-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-ethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 78% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4D) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a) and ethanesulfonyl chloride instead of methanesulfonylchloride in step b).

MS m/e (%): 675 (M+H⁺, 100)

Example 3682-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-chloromethanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 84% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4D) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a) and chloromethylsulfonyl chloride instead of methanesulfonylchloride in step b).

MS m/e (%): 695 (M+H⁺, 100)

Example 3692-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-dimethylsulfamoyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 84% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4D) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramidein step a) and dimethylsulfamoyl chloride instead of methanesulfonylchloride in step b).

MS m/e (%): 695 (M+H⁺, 100)

Example 370(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.20 g (0.38 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,0.11 g (1.1 mmol) (R)-2-methylpiperazine and 0.10 g (0.72 mmol)potassium carbonate in 0.3 ml dimethyl sulfoxide was heated at 180° C.under microwave irradiation in a sealed tube for 30 min. After coolingto room temperature the reaction mixture was diluted with a 0.3 Maqueous solution of sodium hydroxide and extracted with three portionsof tert-butyl methyl ether. The combined organic extracts were driedover sodium sulfate and concentrated. Flash column chromatography gave0.12 g (51%) of the title compound as an off-white solid.

MS m/e (%): 597 (M+H⁺, 100)

b)(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 87% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 675 (M+H⁺, 100)

Example 371(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (R)-1-Benzyl-3-methyl-piperazine

A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol)benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanolwas heated at reflux over night. After cooling to room temperature thereaction mixture was diluted with a 0.5 M aqueous solution of sodiumhydroxide and extracted with three portions of dichloromethane. Thecombined organic extracts were dried over sodium sulfate andconcentrated. Flash column chromatography gave 0.93 g (49%) of the titlecompound as an off-white solid. MS m/e (%): 191 (M+H⁺, 100)

b)(R)-N-[6-(4-Benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

A mixture of 0.20 g (0.38 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,93 mg (0.49 mmol) (R)-1-benzyl-3-methyl-piperazine, 0.01 g (0.03 mmol)cetyltrimethyl-ammonium bromide, 0.038 g (0.074 mmol)bis(tri-t-butylphosphine)palladium(0), 0.05 ml NaOH 50% and 2 ml toluenewas degassed by two freeze-thaw cycles. The reaction mixture was heatedunder argon at 90° C. for 48 h. After cooling to room temperature themixture was diluted with water and brine and extracted with threeportions of tert-butyl methyl ether. The combined organic layers weredried over sodium sulphate and concentrated in vacuo. Flash columnchromatography gave 95 mg (37%) of the title compound as a light yellowsolid. MS m/e (%): 687 (M+H⁺, 100)

c)(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A solution of 0.11 g (0.17 mmol)(R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein 3 ml acetic acid was deoxygenated by three cycles of evacuation andflushing with argon. After addition of 0.02 g palladium on charcoal(10%) the reaction vessel was evacuated and filled with hydrogen gas.The reaction mixture was stirred at room temperature under an atmosphereof hydrogen for 3 h. The reaction mixture was filtered over decalitefollowed by washing with tert-butyl methyl ether. The filtrate waswashed with a 2 M aqueous solution of sodium hydroxide. The aqueouslayer was extracted with three portions of tert-butyl methyl ether. Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to give 98 mg (98%) of the crude title compound as an off-whitesolid, which was used in the next step without further purification. MSm/e (%): 597 (M+H⁺, 100)

d)(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 87% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 675 (M+H⁺, 100)

Example 372(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4A) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 677 (M+H⁺, 100)

Example 373(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide(Intermediate 4G) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 657 (M+H⁺, 100)

Example 374(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 370) using (S)-2-methylpiperazine instead of(R)-2-methylpiperazine in step a).

MS m/e (%): 675 (M+H⁺, 100)

Example 375(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 370) using (S)-2-methylpiperazine instead of(R)-2-methylpiperazine in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4A) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 677 (M+H⁺, 100)

Example 376(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 370) using (S)-2-methylpiperazine instead of(R)-2-methylpiperazine in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide(Intermediate 4G) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 657 (M+H⁺, 100)

Example 377(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing

-   (S)-2-methylpiperazine instead of (R)-2-methylpiperazine in step a).

MS m/e (%): 675 (M+H⁺, 100)

Example 378(2RS,5SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(2RS,5SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(2,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.20 g (0.38 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,87 mg (0.75 mmol) (2RS,5SR)-dimethyl-piperazine, 0.01 g (0.03 mmol)cetyltrimethyl-ammonium bromide, 0.01 g (0.02 mmol)bis(tri-t-butylphosphine)palladium(0), 0.075 ml NaOH 50% and 3 mltoluene was degassed by two freeze-thaw cycles. The reaction mixture washeated under argon at 90° C. for 48 h. After cooling to room temperaturethe mixture was diluted with water and brine and extracted with threeportions of tert-butyl methyl ether. The combined organic layers weredried over sodium sulphate and concentrated in vacuo. Flash columnchromatography gave 96 mg (42%) of the title compound as a light yellowsolid. MS m/e (%): 611 (M+H⁺, 100)

b)(2RS,5SR)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 69% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using(2RS,5SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 689 (M+H⁺, 100)

Example 379(2S,6R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,6-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 1% overall yieldafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing cis-2,6-dimethyl-piperazine instead of (R)-2-methylpiperazine instep a).

MS m/e (%): 689 (M+H⁺, 100)

Example 380(3S,5R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 56% yield afterflash chromatography according to the procedures described above for thepreparation of(2RS,5SR)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,5-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing cis-2,6-dimethyl-piperazine instead of(2RS,5SR)-dimethyl-piperazine in step a).

MS m/e (%): 689 (M+H⁺, 100)

Example 381(1S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-((1S,4S)-5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(1S,4S)-N-[6-(5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 85% yield afterflash chromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramideusing (1S,4S)-(+)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromideinstead of 4-(trifluoromethyl)piperidine hydrochloride.

MS m/e (%): 685 (M+H⁺, 100)

b)(1S,4S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-methanesulfonyl-2,5-diaza-bicycloF 2.2.1 hept-2-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 80% yield afterflash chromatography according to the procedures described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 371 steps c) and d)) using(1S,4S)-N-[6-(5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramidein step c).

MS m/e (%): 673 (M+H⁺, 100)

Example 382(1R,5S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(8-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(1S,4S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane dihydrochlorideinstead of (1S,4S)-(+)-2-benzyl-2,5-diazabicyclo[2.2.1]heptanedihydrobromide in step a). MS m/e (%): 687 (M+H⁺, 100)

Example 383(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)(S)-N-[6-(2-Benzyloxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in comparableyields according to the procedures described above for the preparationof(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 371c)) using (S)-1-benzyl-3-(benzyloxymethyl)piperazine(prepared as described in WO2001009111) instead of(R)-1-benzyl-3-methyl-piperazine in step b). MS m/e (%): 703 (M+H⁺, 100)

b)(S)-N-[6-(2-Benzyloxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 89% yield afterflash chromatography according to the procedures described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using(S)-N-[6-(2-benzyloxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 781 (M+H⁺, 100)

c)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in 72% yield afterflash chromatography according to the procedures described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 152b)) using(S)-N-[6-(2-benzyloxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(1R,2R)-N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 691 (M+H⁺, 100)

Example 384(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-formyl-2-hydroxymethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A mixture of 0.35 ml (3.7 mmol) acetic anhydride and 0.17 ml (4.6 mmol)formic acid was heated at 50° C. for 2 h. After cooling to roomtemperature a portion of 0.08 ml of this mixture was added to 0.5 mlTHF. A solution of 0.10 g (0.14 mmol)(S)-N-[6-(2-benzyloxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide(Example 383a)) in 1 ml THF was added dropwise at 0° C. Conversion wasmonitored by thin layer chromatography. After complete consumption ofthe starting material the reaction mixture was diluted with water andextracted with three portions of dichloromethane. The combined organicextracts were dried over sodium sulfate and concentrated in vacuo togive 0.11 g of crude(S)-N-[6-(2-benzyloxymethyl-4-formyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideas a light yellow solid.

The title compound was obtained as a white solid in 58% yield afterflash chromatography according to the procedure described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 152b)) using crude(S)-N-[6-(2-benzyloxymethyl-4-formyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(1R,2R)-N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 641 (M+H⁺, 100)

Example 385(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-cyclopropanecarbonyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing cyclopropanecarboxylic acid chloride instead of methanesulfonylchloride in step b).

MS m/e (%): 681 (M+H⁺, 100)

Example 386(S)-N-[6-(4-Acetyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing acetic anhydride instead of methanesulfonyl chloride in step b).

MS m/e (%): 655 (M+H⁺, 100)

Example 387(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-ethyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidea)(S)-N-[6-(2-Benzyloxymethyl-4-ethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a light brown solid in 5% yield instep c) according to the procedures described above for the preparationof(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 371c)) using (S)-1-benzyl-3-(benzyloxymethyl)piperazine(prepared as described in WO2001009111) instead of(R)-1-benzyl-3-methyl-piperazine in step b) and ethanol instead ofacetic acid as a solvent in step c). MS m/e (%): 731 (M+H⁺, 100)

b)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-ethyl-2-hydroxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 58% yield afterflash chromatography according to the procedure described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 152b)) using(S)-N-[6-(2-benzyloxymethyl-4-ethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(1R,2R)-N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 641 (M+H⁺, 100)

Example 3882-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfamoyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)2-[5-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(2-chloro-phenyl)-pyridin-2-ylamino]-ethanesulfonicAcid

The title compound was obtained as a light brown solid in 49% yieldafter flash column chromatography according to the procedure describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 165) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide(Intermediate 4A) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand taurine instead of L-prolinol.

MS m/e (%): 622 ([M−H⁺]⁻, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfamoyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 77% yield afterflash column chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-dimethylsulfamoyl-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 331 step c)) using a 12 M aqueous solution of N-methylamineinstead of a solution of dimethylamine.

MS m/e (%): 637 (M+H⁺, 100)

Example 3892-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methyl-1,1-dioxo-1λ⁶-[1,2,4]thiadiazinan-4-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 31% yield afterflash chromatography according to the procedure described above for thepreparation of(RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxymethyl-oxazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 342) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfamoyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-1-hydroxymethyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide.

MS m/e (%): 649 (M+H⁺, 100)

Example 390(RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-2λ⁴-[1,2,3]oxathiazolidin-3-yl)-pyridin-3-yl]-N-methyl-isobutyramide

To a solution of 0.20 g (0.36 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidein a 5 ml dichloromethane were added consecutively 0.11 g (1.1 mmol)triethylamine and 0.05 g (0.4 mmol) thionyl chloride at roomtemperature. After 1 h the reaction mixture was diluted with water andextracted with three portions of dichloromethane. The combined organicextracts were dried over sodium sulfate and concentrated in vacuo. Flashcolumn chromatography gave 0.17 g (77%) of the title compound as a whitesolid.

MS m/e (%): 606 (M+H⁺, 100)

Example 391(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea) (S)-4-Benzyl-2-benzyloxymethyl-1-methanesulfonyl-piperazine

The crude title compound was obtained as a light brown oil inquantitative yield after extraction according to the procedure describedabove for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using (S)-1-benzyl-3-(benzyloxymethyl)piperazine insteadof2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 375 (M+H⁺, 100)

b) (S)-2-Benzyloxymethyl-1-methanesulfonyl-piperazine

The crude title compound was obtained as a light brown oil in 60% yieldafter extraction according to the procedure described above for thepreparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 371c)) using(S)-4-benzyl-2-benzyloxymethyl-1-methanesulfonyl-piperazine instead of(R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 285 (M+H⁺, 100)

c)(S)-N-[6-(3-Benzyloxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide

The title compound was obtained as a white solid in 55% yield afterflash chromatography according to the procedure described above for thepreparation of(R)-N-[6-(4-benzyl-2-methyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide(Example 371b)) using (S)-2-benzyloxymethyl-1-methanesulfonyl-piperazineinstead of (R)-1-benzyl-3-methyl-piperazine.

MS m/e (%): 781 (M+H⁺, 100)

d)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 96% yield afterflash chromatography according to the procedure described above for thepreparation of(1R,2R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-cyclopentylamino)-pyridin-3-yl]-N-methyl-isobutyramide(Example 152b)) using(S)-N-[6-(3-benzyloxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramideinstead of(1R,2R)-N-[6-(2-benzyloxy-cyclopentylamino)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.

MS m/e (%): 691 (M+H⁺, 100)

Example 392(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as white solid in comparable yieldsafter flash column chromatography according to the procedures describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (R)-instead of (S)-1-benzyl-3-(benzyloxymethyl)piperazine in stepa) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide(Intermediate 4G) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step c).

MS m/e (%): 673 (M+H⁺, 100)

Example 393(R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as white solid in comparable yieldsafter flash column chromatography according to the procedures describedabove for the preparation of(S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxymethyl-4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing (R)- instead of (S)-1-benzyl-3-(benzyloxymethyl)piperazine in stepa). MS m/e (%): 691 (M+H⁺, 100)

Example 3942-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3,3-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a light brown amorphous resin in 27%yield after flash column chromatography according to the proceduredescribed above for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide(Example 323) using 2,2-dimethyl-piperazine di-acetic acid salt insteadof 4-(trifluoromethyl)piperidine hydrochloride.

MS m/e (%): 611 (M+H⁺, 100)

b)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in 69% yield afterflash column chromatography according to the procedure described abovefor the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 689 (M+H⁺, 100)

Example 3952-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as white solid in comparable yieldsafter flash column chromatography according to the procedures describedabove for the preparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3,3-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide(Intermediate 4G) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step a).

MS m/e (%): 671 (M+H⁺, 100)

Example 396(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-hydroxymethyl-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white solid in comparable yieldsafter flash chromatography according to the procedures described abovefor the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide(Example 370) using (S)-2-methylpiperazine instead of(R)-2-methylpiperazine in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl}-N-methyl-isobutyramide(Intermediate 4L) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 787 (M+H⁺, 100)

b)(S)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-hydroxymethyl-phenyl)-6-(−4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

A solution of 73 mg (0.093 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidein 5 ml of a 1 M solution of hydrochloric acid in methanol was stirredat room temperature. Conversion was monitored by thin layerchromatography. After complete consumption of the starting material thereaction mixture was diluted with a 1 M aqueous solution of sodiumhydroxide and extracted with three portions of tert-butyl methyl ether.The combined organic extracts were dried over sodium sulfate andconcentrated in vacuo. Flash column chromatography gave 62 mg(quantitative) of the title compound as a light yellow solid.

MS m/e (%): 673 (M+H⁺, 100)

Example 3972-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,2-dimethyl-piperazine di-acetic acid salt instead of(R)-2-methyl-piperazine in step a).

MS m/e (%): 689 (M+H⁺, 100)

Example 3982-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-2,2-dimethyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as an off-white solid in comparableyields after flash chromatography according to the procedures describedabove for the preparation of(R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-2-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramideusing 2,2-dimethyl-piperazine di-acetic acid salt instead of(R)-2-methyl-piperazine in step a) and2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide(Intermediate 4G) instead of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramidein step b).

MS m/e (%): 671 (M+H⁺, 100)

Example 399(S)-2-(3,5-Dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-(3,5-dimethoxy-phenyl)-2-methyl-propionyl chloride as a white solid.

MS m/e (%): 439 (M+H⁺, 100).

b)(S)-2-(3,5-Dimethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand L-prolinol as a light yellow foam.

MS m/e (%): 504 (M+H⁺, 100).

Example 400(2S,4R)-2-(3,5-Dimethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 520 (M+H⁺, 100).

Example 4012-(3,5-Dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-dimethoxy-phenyl)-2-methyl-propionyl chloride as a white solid.

MS m/e (%): 457 (M+H⁺, 100).

b)2-(3,5-Dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1b) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand ethanolamine as an off-white foam.

MS m/e (%): 482 (M+H⁺, 100).

Example 402(S)-2-(3,5-Dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 522 (M+H⁺, 100).

Example 403(2S,4R)-2-(3,5-Dimethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 538 (M+H⁺, 100).

Example 404(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramidea)N-[6-Chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and2-(3,5-dimethoxy-phenyl)-2-methyl-propionyl chloride as a light yellowsolid.

MS m/e (%): 459 (M+H⁺, 100).

b)(2S,4R)-N-[4-(2-Chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 540 (M+H⁺, 100).

Example 4052-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dihydroxy-phenyl)-N-methyl-isobutyramide

To a solution of 2.8 g (6.4 mmol)N-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramidein 70 ml CH₂Cl₂ 19 ml (19 mmol) BBr₃ (1 M in CH₂Cl₂) were added at 0° C.The reaction mixture was allowed to reach ambient temperature andstirred for 15 h After addition of 50 ml water the mixture was extractedwith three portions of dichloromethane. The combined organic extractswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash-chromatography (SiO₂, CH₂Cl₂/methanol) to give 2.5 g (95%) ofthe title compound as a white foam.

MS m/e (%): 409 (M+H⁺, 87).

b)2-(3,5-Bis-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide

To a solution of 2.5 g (6.1 mmol)N-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dihydroxy-phenyl)-N-methyl-isobutyramidein 60 ml DMF 1.7 g (12 mmol) K₂CO₃ and 1.5 ml (12 mmol) ethylchlordifluoroacetate were added and the resulting suspension heated at65° C. for 15 h. After cooling to ambient temperature, the reactionmixture was poured into 250 ml water and extracted with three portionsof CH₂Cl₂. The combined organic extracts were dried (Na₂SO₄), filteredand evaporated. The residue was purified by flash-chromatography (SiO₂,CH₂Cl₂/ethyl acetate) to give 0.71 g (23%) of the title compound as acolorless viscous oil.

MS m/e (%): 511 (M+H⁺, 100).

c)2-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxy-ethylamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1b) from2-(3,5-bis-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand ethanolamine as an off-white foam.

MS m/e (%): 536 (M+H⁺, 100).

Example 406(2S,4R)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3,5-bis-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 592 (M+H⁺, 100).

Example 407(S)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-(2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3,5-bis-difluoromethoxy-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 576 (M+H⁺, 100).

Example 4082-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 406a), b) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideas a colorless oil.

MS m/e (%): 529 (M+H⁺, 100).

b)2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1b) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand ethanolamine as a white foam.

MS m/e (%): 554 (M+H⁺, 100).

Example 409(S)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand L-prolinol as a light brown foam.

MS m/e (%): 594 (M+H⁺, 100).

Example 410(2S,4R)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramidea)2-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 406a), b) fromN-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramideas a colorless oil.

MS m/e (%): 531 (M+H⁺, 100).

b)(2S,4R)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 612 (M+H⁺, 100).

Example 411(S)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand L-prolinol as a white foam.

MS m/e (%): 596 (M+H⁺, 100).

Example 4122-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1b) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand ethanolamine as a white foam.

MS m/e (%): 556 (M+H⁺, 100).

Example 413(2S,4R)-2-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a light yellowfoam.

MS m/e (%): 610 (M+H⁺, 100).

Example 414(2S,4R)-N-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramidea)N-(6-Chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from (6-chloro-4-o-tolyl-pyridin-3-yl)-methyl-amine and2-methyl-2-(3-trifluoromethoxy-phenyl)-propionyl chloride (Intermediate5I) as a light yellow oil.

MS m/e (%): 462 (M⁺, 8).

b)(2S,4R)-N-[6-(4-Hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 544 (M+H⁺, 100).

Example 415(2S,4R)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramidea)N-[6-Chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 1a) from[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and2-methyl-2-(3-trifluoromethoxy-phenyl)-propionyl chloride (Intermediate5I) as white solid.

MS m/e (%): 481 (M+H⁺, 100).

b)(2S,4R)-N-[4-(4-Fluoro-2-methyl-phenyl)-6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 3) fromN-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramideand (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine as a white foam.

MS m/e (%): 562 (M+H⁺, 100).

Example 4162-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand piperazine instead of L-prolinol as a light yellow foam.

MS m/e (%): 581 (M+H⁺, 100).

Example 4172-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) from2-(3,5-bis-difluoromethoxy-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramideand piperazine instead of L-prolinol as an off-white foam.

MS m/e (%): 579 (M+H⁺, 100).

Example 4182-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 84% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(2-chloro-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 659 (M+H⁺, 100)

Example 4192-(3,5-Bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 88% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using2-(3,5-bis-difluoromethoxy-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-piperazin-1-yl-pyridin-3-yl]-N-methyl-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 657 (M+H⁺, 100)

Example 4202-(3,5-Bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide

The title compound was obtained in an analogous manner to that describedin example 2) fromN-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-2-(3-trifluoromethoxy-phenyl)-isobutyramideand piperazine instead of L-prolinol as a light yellow foam.

MS m/e (%): 561 (M+H⁺, 100).

Example 4212-(3,5-Bis-difluoromethoxy-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide

The title compound was obtained as a white foam in 61% yield after flashchromatography according to the procedure described above for thepreparation of2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide(Example 362b)) using2-(3,5-bis-difluoromethoxy-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramideinstead of2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.

MS m/e (%): 639 (M+H⁺, 100)

Example A

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

Example B

Capsules of the following composition are manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatine capsules.

Example C

Suppositories of the following composition are manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool, the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

1. A method of treating schizophrenia comprising administering to anindividual an effective amount of a compound of formula I

wherein R¹ is aryl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′ S(O)₂-alkyl, or isheteroaryl, selected from the group consisting of pyridin-2- or 3-yl,imidazolyl and oxazolyl, each of which is unsubstituted or substitutedby alkyl, halogen or alkoxy; R² and R³ are each independently hydrogen,halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃; R⁴ and R⁵ are eachindependently hydrogen, —(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each carbonatom are the same or different, —C_(b)-alkyl, —C(O)H,—(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy,—(CH₂)_(c)NR′R″, —(CH₂)_(c)NR′C(O)-alkyl, —(CH₂)_(c)NR′S(O)₂-alkyl,—(CH₂)_(d)S(O)-alkyl, —(CH₂)_(d)S-alkyl, (CH₂)_(d)S(O)₂-alkyl, or—(CH₂)_(d)S(O)₂—NR′R″; R′ is hydrogen, alkyl, —(CH₂)_(o)OH, —C(O)H,—C(O)-alkyl, —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl,—S(O)-alkyl, —S-alkyl or —S(O)₂—N-di-alkyl, R″ is hydrogen or alkyl; orR⁴ and R⁵ form together with the N-atom to which they are attached aring with —(CH₂)_(e)—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl, or —C(O)NR′R″, or with—(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—(CH₂)_(c)—S(O)_(f)—(CH₂)_(c)—, which is unsubstituted or substituted byone or more substituents selected from the group consisting of alkyl,halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″are as described above or together with the N-atom to which they areattached form a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—CH₂CH═CH—CH₂—, which is unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, halogen, CF₃,—(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as describedabove or together with the N-atom to which they are attached form a ringwith —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; or with—(CH₂)₂—S(O)₂N(CH₃)—CH₂, or with —S(O)—O—(CH₂)_(2,3)—; or —NR⁴R⁵ is

a is 0 or 1; b is 1 or 2; c is 1, 2, or 3; d is 0, 1, 2, or 3; e is 3,4, or 5; and f is 0, 1, or 2; or a pharmaceutically active acid-additionsalt thereof.
 2. The method of claim 1, wherein the compound of formulaI is a compound of formula IA

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ are each independently hydrogen,—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH, or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each carbonatom are the same or different and are hydrogen, or C_(b)-alkyl; R′ ishydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl,—S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl, —S-alkyl or—S(O)₂—N-di-alkyl, R″ is hydrogen or alkyl; a is 0 or 1; b is 1 or 2;and d is 0, 1, 2 or 3; or a pharmaceutically acceptable acid additionsalt thereof.
 3. The method of claim 1, wherein the compound of formulaI is a compound of formula IB

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ are each independently hydrogen, —(CH₂)₂SCH₃,—(CH₂)₂S(O)₂CH₃, —(CH₂)₂S(O)₂NHCH₃, —(CH₂)₂NH₂, —(CH₂)₂NHS(O)₂CH₃, or—(CH₂)₂NHC(O)CH₃; R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H,—C(O)-alkyl, —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl,—S(O)-alkyl, —S-alkyl or —S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; bis 1 or 2; and d is 0, 1, 2, or 3; or a pharmaceutically activeacid-addition salt thereof.
 4. The method of claim 1, wherein thecompound of formula I is a compound of formula IC

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ is hydrogen; R⁵ is —(CH₂)_(o)-cycloalkyl, unsubstituted orsubstituted by hydroxy; R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H,—C(O)-alkyl, —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl,—S(O)-alkyl, —S-alkyl or —S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; bis 1 or 2; and d is 0, 1, 2, or 3; or a pharmaceutically activeacid-addition salt thereof.
 5. The method of claim 1, wherein thecompound of formula I is a compound of formula ID

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ form together with the N-atom to which they areattached a ring with —(CH₂)_(e)—, which is unsubstituted or substitutedby one or more substituents selected from the group consisting of—(CR′R″)_(d)OH; R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H,—C(O)-alkyl, —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl,—S(O)-alkyl, —S-alkyl or —S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; bis 1 or 2; d is 0, 1, 2, or 3; and e is 3, 4, or 5; or apharmaceutically active acid-addition salt thereof.
 6. The method ofclaim 1, wherein the compound of formula I is a compound of formula IE

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ form together with the N-atom to which they areattached a ring with —(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″,wherein R′ and R″ together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl,—(CH₂)_(d)—OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinylor —C(O)NR′R″; R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,—C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,—S-alkyl or —S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; b is 1 or 2; cis 1, 2, or 3; d is 0, 1, 2, or 3; and e is 3, 4, or 5; or apharmaceutically active acid-addition salt thereof.
 7. The method ofclaim 1, wherein the compound of formula I is a compound of formula IF

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl, or isheteroaryl selected from the group consisting of pyridin-2- or 3-yl,imidazolyl and oxazolyl, each of which is unsubstituted or substitutedby alkyl, halogen or alkoxy; R² and R³ are each independently hydrogen,halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃; and R⁴ and R⁵ formtogether with the N-atom to which they are attached a ring with—(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of lower alkyl,halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein R′ and R″ together withthe N-atom to which they are attached form a ring with —(CH₂)_(e), or by—(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; R′ ishydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl,—S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl, —S-alkyl or—S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; b is 1 or 2; c is 1, 2, or3; d is 0, 1, 2, or 3; and e is 3, 4, or 5; or a pharmaceutically activeacid-addition salt thereof.
 8. The method of claim 1, wherein thecompound of formula I is a compound of formula IG

wherein R¹ is phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl and —NR′S(O)₂-alkyl; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ form together with the N-atom to which they areattached a ring with —(CH₂)_(c)—S(O)_(f)—(CH₂)₂—, which is unsubstitutedor substituted by one or more substituents selected from the groupconsisting of lower alkyl, halogen, —(CR′R″)_(d)OH, ═O, and —NR′Rwherein R′ and R″ together with the N-atom to which they are attachedform a ring with —(CH₂)_(d), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; R′ ishydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl,—S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl, —S-alkyl or—S(O)₂—N-di-alkyl; R″ is hydrogen or alkyl; b is 1 or 2; c is 1, 2, or3; d is 0, 1, 2, 3 or 4; e is 3, 4, or 5; and f is 0, 1, or 2; or apharmaceutically active acid-addition salt thereof.
 9. The method ofclaim 1, wherein the compound of formula I is a compound of formula IH

wherein R¹ is heteroaryl selected from the group consisting ofpyridin-2- or 3-yl, imidazolyl and oxazolyl, each of which isunsubstituted or substituted by alkyl, halogen or alkoxy; R² and R³ areeach independently hydrogen, halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃or CF₃; R⁴ and R⁵ are each independently hydrogen,—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)—OH or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-alkyl, wherein R′ and R″ on each carbonatom are the same or different, —C_(b)-alkyl, —C(O)H,—(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy,—(CH₂)_(c)NR′R″, —(CH₂)_(c)NR′C(O)-alkyl, —(CH₂)_(c)NR′S(O)₂-alkyl,—(CH₂)_(d)S(O)-alkyl, —(CH₂)_(d)S-alkyl, —(CH₂)_(d)S(O)₂-alkyl, or—(CH₂)_(d)S(O)₂—NR′R″; R′ is hydrogen, alkyl, —(CH₂)_(o)OH, —C(O)H,—C(O)-alkyl, —C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl,—S(O)-alkyl, —S-alkyl or —S(O)₂—N-di-alkyl, R″ is hydrogen or alkyl; orR⁴ and R⁵ form together with the N-atom to which they are attached aring with —(CH₂)_(e)—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl, or —C(O)NR′R″, or with—(CH₂)_(c)—NR′—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are asdescribed above or together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—(CH₂)_(c)—S(O)_(f)—(CH₂)_(c)—, which is unsubstituted or substituted byone or more substituents selected from the group consisting of alkyl,halogen, CF₃, —(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″are as described above or together with the N-atom to which they areattached form a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl,—(CH₂)_(d)—C(O)-alkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—CH₂CH═CH—CH₂—, which is unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, halogen, CF₃,—(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as describedabove or together with the N-atom to which they are attached form a ringwith —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-alkyl, —(CH₂)_(d)—C(O)-alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-alkyl, —(CH₂)_(d)—S(O)-alkyl, —(CH₂)_(d)—S-alkyl,—(CH₂)_(d)—S(O)₂—NR′R″, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; or with—(CH₂)₂—S(O)₂N(CH₃)—CH₂, or with —S(O)—O—(CH₂)_(2,3)—; or —NR⁴R⁵ is

a is 0 or 1; b is 1 or 2; c is 1, 2, or 3; d is 0, 1, 2, or 3; e is 3,4, or 5; and f is 0, 1, or 2; or a pharmaceutically active acid-additionsalt thereof.
 10. The method of claim 1, wherein the compound of formulaI is a compound of formula I J,

wherein R¹ is aryl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl, or isheteroaryl, selected from the group, consisting of pyridin-2- or 3-yl,imidazolyl and oxazolyl, each of which is unsubstituted or substitutedby alkyl, halogen or alkoxy; R² and R³ are each independently hydrogen,halogen, alkyl, alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃; —NR⁴R⁵ is

R′ is hydrogen, alkyl, —(CH₂)_(d)OH, —C(O)H, —C(O)-alkyl,—C(O)-cycloalkyl, —S(O)₂-alkyl, —S(O)₂-halogen-alkyl, —S(O)-alkyl,—S-alkyl or —S(O)₂—N-di-alkyl, R″ is hydrogen or alkyl; b is 1 or 2; dis 0, 1, 2, or 3; and f is 0, 1, or 2; or a pharmaceutically activeacid-addition salt thereof.
 11. The method of claim 1, wherein thecompound of formula I is a compound of formula I-1

wherein R¹ is aryl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, alkoxy,halogen, —(CH₂)_(d)OH, —C(O)H, CF₃, CN, S-alkyl, —S(O)_(b)-alkyl,—C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)₂-alkyl, or isheteroaryl, selected from the groups consisting of pyridin-2- or 3-yl,imidazolyl or oxazolyl, each of which is unsubstituted or substituted byalkyl, halogen or alkoxy; R² and R³ are each independently hydrogen,halogen, lower alkyl, lower alkoxy, OCHF₂, OCH₂F, OCF₃ or CF₃; R⁴ and R⁵are each independently hydrogen, —(CR′R″)₁—(C—FR′R″)₁—(CR′R″)_(a)—OH or—(CR′R″)₁—(CR′R″)₁—(CR′R″)_(a)-lower alkyl, wherein R′ and R″ on eachcarbon atom are the same or different, —C_(b)-alkyl, —C(O)H,—(CH₂)_(d)cycloalkyl, unsubstituted or substituted by hydroxy,—(CH₂)_(c)NR′C(O)-lower alkyl, —(CH₂)_(c)NR′S(O)₂-lower alkyl, or—(CH₂)_(d)S(O)₂-lower alkyl; R′ is hydrogen, lower alkyl, —(CH₂)_(o)OH,—C(O)H, —C(O)-lower alkyl, —C(O)-cycloalkyl, —S(O)₂-lower alkyl; R″ ishydrogen or lower alkyl; or R⁴ and R⁵ form together with the N-atom towhich they are attached a ring with —(CH₂)_(e)—, which is unsubstitutedor substituted by one or more substituents selected from the groupconsisting of lower alkyl, halogen, CF₃, —(CR′R″)_(d)OH, ═O, and —NR′R″,wherein R′ and R″ together with the N-atom to which they are attachedform a ring with —(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-cycloalkyl,—(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-lower alkyl,—(CH₂)_(d)-pyrrolidinyl, or —C(O)NR′R″, or with —(CH₂)_(c)—NR′—(CH₂)₂—,which is unsubstituted or substituted by one or more substituentsselected from the group consisting of lower alkyl, halogen,—(CR′R″)_(d)OH, ═O, —CHO, and —NR′R″, wherein R′ and R″ together withthe N-atom to which they are attached form a ring with —(CH₂)_(e), or by—(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂—loweralkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—(CH₂)_(c)—O—(CH₂)₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of lower alkyl,halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein R′ and R″ together withthe N-atom to which they are attached form a ring with —(CH₂)_(e), or by—(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-loweralkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, or with—(CH₂)_(c)—S(O)_(f)—(CH₂)_(c)—, which is unsubstituted or substituted byone or more substituents selected from the group consisting of loweralkyl, halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein R′ and R″together with the N-atom to which they are attached form a ring with—(CH₂)_(e), or by —(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-loweralkyl, —(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″,—(CH₂)_(d)—S(O)₂-lower alkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″, orwith —CH₂CH═CH—CH₂—, which is unsubstituted or substituted by one ormore substituents selected from the group consisting of lower alkyl,halogen, —(CR′R″)_(d)OH, ═O, and —NR′R″, wherein R′ and R″ together withthe N-atom to which they are attached form a ring with —(CH₂)_(e), or by—(CH₂)_(d)NR′—C(O)-lower alkyl, —(CH₂)_(d)—C(O)-lower alkyl,—(CH₂)_(d)—C(O)-cycloalkyl, —(CH₂)_(d)OC(O)NR′R″, —(CH₂)_(d)—S(O)₂-loweralkyl, —(CH₂)_(d)-pyrrolidinyl or —C(O)NR′R″; a is 0 or 1; b is 1 or 2;c is 1, 2, or 3; d is 0, 1, 2, or 3; e is 3, 4, or 5; and f is 0, 1, or2; or a pharmaceutically active acid-addition salt thereof.